Almanza Et Al 2018 - Endoplasmic Reticulum Stress Signalling From Basic Mechanisms To Clinical

REVIEW ARTICLE
Endoplasmic reticulum stress signalling – from basic

mechanisms to clinical applications
Aitor Almanza1, Antonio Carlesso2, Chetan Chintha1, Stuart Creedican3, Dimitrios Doultsinos4,5,
Brian Leuzzi1, Andreia Luıs6, Nicole McCarthy7, Luigi Montibeller8, Sanket More9, Alexandra
Papaioannou4,5, Franziska Pu € schel10, Maria Livia Sassano9, Josip Skoko11, Patrizia Agostinis9,
Jackie de Belleroche , Leif A. Eriksson2, Simone Fulda7, Adrienne M. Gorman1 , Sandra Healy1,
8
Andrey Kozlov6, Cristina Mun ~ oz-Pinedo10 , Markus Rehm11, Eric Chevet4,5 and Afshin Samali1
1 Apoptosis Research Centre, National University of Ireland, Galway, Ireland
2 Department of Chemistry and Molecular Biology, University of Gothenburg, Go €teborg, Sweden
3 Randox Teoranta, Dungloe, County Donegal, Ireland
4 INSERM U1242, University of Rennes, France
5 Centre de Lutte Contre le Cancer Eugene Marquis, Rennes, France
6 Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, AUVA Research Centre, Vienna, Austria
7 Institute for Experimental Cancer Research in Paediatrics, Goethe-University, Frankfurt, Germany
8 Neurogenetics Group, Division of Brain Sciences, Faculty of Medicine, Imperial College London, UK
9 Department Cellular and Molecular Medicine, Laboratory of Cell Death and Therapy, KU Leuven, Belgium
10 Cell Death Regulation Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain
11 Institute of Cell Biology and Immunology, University of Stuttgart, Germany
Keywords The endoplasmic reticulum (ER) is a membranous intracellular organelle

endoplasmic reticulum; proteostasis; and the first compartment of the secretory pathway. As such, the ER con-
signalling pathway; stress
tributes to the production and folding of approximately one-third of cellu-
lar proteins, and is thus inextricably linked to the maintenance of cellular
Correspondence
E. Chevet, INSERM U1242, Centre de Lutte homeostasis and the fine balance between health and disease. Specific ER
Contre le Cancer Euge ne Marquis, Avenue stress signalling pathways, collectively known as the unfolded protein
de la bataille Flandres Dunkerque, 35042 response (UPR), are required for maintaining ER homeostasis. The UPR
Rennes, France is triggered when ER protein folding capacity is overwhelmed by cellular
Abbreviations
4-PBA, 4-phenylbutyric acid; ALS, amyotrophic lateral sclerosis; ATF4, activating transcription factor 4; ATF6f, cytosolic domain of ATF6;
ATF6a, activating transcription factor 6 a; ATF6b, activating transcription factor 6 b; BBF2H7, cAMP responsive element-binding protein 3
like 2; BiP, binding immunoglobulin protein (gene GRP78); bZIP, basic-leucine zipper; CHOP, CAAT/enhancer-binding protein (C/EBP)
homologous protein; CRCL, chaperone-rich cell lysate; CREB3L3, cAMP responsive element-binding protein 3 like 3; CREB, cAMP response
element-binding protein; eIF2B, eukaryotic translation initiation factor 2B; eIF2a, eukaryotic translation initiation factor 2a; ERAD, ER-
associated protein degradation; ER, endoplasmic reticulum; ERN1, endoplasmic reticulum to nucleus signalling 1; ERN2, endoplasmic
reticulum to nucleus signalling 2; ERO-1, ER oxidoreductin 1; ERa, oestrogen receptor a; GADD34, growth arrest and DNA-damage-
inducible 34; GRP78, glucose-regulated protein 78; GSH, glutathione; IBD, inflammatory bowel disease; IRE1a, inositol-requiring enzyme 1
a; IRE1b, inositol-requiring enzyme 1 b; LUMAN, cAMP responsive element-binding protein 3 or CREB3; MAM, mitochondria-associated
membrane; MBTPS1, membrane bound transcription factor peptidase, site 1; MBTPS2, membrane bound transcription factor peptidase, site
2; MDM1/SNX13, mitochondrial distribution and morphology 1/sorting nexin 13; mTOR, mammalian target of rapamycin; N-ATF6, N-terminal
portion of ATF6 or ATF6f; NF-Y, nuclear transcription factor Y; NGLY1, N-glycanase; NPR, NADPH-P450 reductase; OASIS, cAMP
responsive element-binding protein 3 like 1; ORAI1, calcium release-activated calcium channel protein 1; PDI, protein disulfide isomerase;
p-eIF2a, phospho-eIF2a; PERK, protein kinase RNA-like (PKR-like) endoplasmic reticulum kinase; PKR, protein kinase RNA-activated; PM,
plasma membrane; PP1, protein phosphatase type 1; qPCR, quantitative polymerase chain reaction; RER, rough endoplasmic reticulum;
RIDD, regulated IRE1-dependent decay; ROS, reactive oxygen species; SEC22b, vesicle-trafficking protein SEC22b; SERCA, sarco/
endoplasmic reticulum ATPase Ca2+-ATPase; SER, smooth endoplasmic reticulum; TAD, transcriptional activation domain; TRAF2, tumour
necrosis factor receptor-associated factor 2; TUDCA, tauroursodeoxycholic acid; UDCA, ursodeoxycholic acid; UPR, unfolded protein
response; WT, wild-type; XBP1s, spliced isoform of XBP1; XBP1u, unspliced isoform of XBP1; XBP1, X-box binding protein 1.
The FEBS Journal 286 (2019) 241–278 ª 2018 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of 241
Federation of European Biochemical Societies.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use,
distribution and reproduction in any medium, provided the original work is properly cited.
Compendium of endoplasmic reticulum stress signaling A. Almanza et al.
Fax: +33 (0)299253164 demand and the UPR initially aims to restore ER homeostasis and normal
Tel: +33 (0)223237258 cellular functions. However, if this fails, then the UPR triggers cell death.
E-mail: [email protected]
In this review, we provide a UPR signalling-centric view of ER functions,
A. Samali, Apoptosis Research Centre,
from the ER’s discovery to the latest advancements in the understanding
Biomedical Sciences, NUI Galway, Dangan,
Galway, Ireland of ER and UPR biology. Our review provides a synthesis of intracellular
Fax: +353 91 494596 ER signalling revolving around proteostasis and the UPR, its impact on
Tel: +353 91 492440 other organelles and cellular behaviour, its multifaceted and dynamic
E-mail: [email protected] response to stress and its role in physiology, before finally exploring the
potential exploitation of this knowledge to tackle unresolved biological
Aitor Almanza, Antonio Carlesso, Chetan
questions and address unmet biomedical needs. Thus, we provide an inte-
Chintha, Stuart Creedican, Dimitrios
grated and global view of existing literature on ER signalling pathways
Doultsinos, Brian Leuzzi, Andreia Luıs,
Nicole McCarthy, Luigi Montibeller, Sanket and their use for therapeutic purposes.
More, Alexandra Papaioannou, Franziska
€schel, Maria Livia Sassano and Josip
Pu
Skoko contributed equally to this work and
are listed in alphabetical order.
(Received 18 March 2018, revised 24 June

2018, accepted 18 July 2018)
doi:10.1111/febs.14608
Introduction whereby ER tubules possess a high membrane curva-

ture compared to the sheets of the nuclear envelope
The endoplasmic reticulum (ER) is a cellular orga-
and cisternae. The ER occupies an extensive cell-type-
nelle that was first visualized in chicken fibroblast-like
specific footprint within the cell and is in contact with
cells using electron microscopy and was described as
many other intracellular organelles. It forms physical
a ‘delicate lace-work extending throughout the cyto-
contact sites with mitochondria named mitochondria-
plasm’ [1]. Its current name was coined almost
associated membranes (MAMs), which play a crucial
10 years later by Porter in 1954 [2]. The ER appears
role in Ca2+ homeostasis [6]. It also comes in contact
as a membranous network of elongated tubules and
with the plasma membrane (PM), an interaction regu-
flattened discs that span a great area of the cyto-
lated by proteins like stromal interaction molecule 1 in
plasm [3]. This membrane encloses the ER lumen and
the ER and calcium release-activated calcium channel
allows for the transfer of molecules to and from the
protein 1 in the PM which are controlled by Ca2+
cytoplasm.
levels [7]. Vesicle-trafficking protein SEC22b (SEC22b)
and vesicle-associated membrane protein 7 are also
involved in the stabilization of ER-PM contacts and
ER structure
PM expansion [8]. The ER also interacts with endo-
The ER is classically divided into the rough ER somes [9] and is tethered by StAR-related lipid transfer
(RER) and smooth ER (SER), depending on the pres- protein 3 and StAR-related lipid transfer protein 3
ence or absence of ribosomes on the cytosolic face of [10], which also contribute to cholesterol maintenance
the membrane respectively. The SER and RER can in endosomes [11]. Interestingly, an ER interaction
exist either as interconnected or spatially separated with the endolysosomal system, mediated by the mito-
compartments [4]. More recently, a novel classification chondrial distribution and morphology 1/sorting nexin
was proposed based on membrane structure rather 13 (MDM1/SNX13) complex [12], suggests ER
than appearance. According to this classification, the involvement in autophagy. Indeed, a specialized ER
ER comprises the nuclear envelope, sheet-like cisternae structure called the omegasome forms contact sites
and a polygonal array of tubules connected by three- with the phagophore, which elongates and becomes a
way junctions [5]. A striking difference between these mature autophagosome [13,14] (Fig. 1). In this way,
ER structures is the curvature of the membrane, the ER on its own or in coordination with other cell
242 The FEBS Journal 286 (2019) 241–278 ª 2018 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of
A. Almanza et al. Compendium of endoplasmic reticulum stress signaling
Fig. 1. ER molecular machines and contact sites with other organelles. The ER is primarily subdivided into the SER and RER, with the latter
characterized by the presence of ribosomes at its cytosolic surface. Alternatively, the ER has been recently classified into the nuclear
envelope, ER sheet-like cisternae and tubular ER (panel 1). The ER forms multiple membrane contact sites with other organelles, including
the endosomes and lysosomes (through STARD3, STARD3NL, Mdm1; panel 2), the mitochondria (through Mfn-2, Sig-1R, PERK; panel 3),
and the PM (through ORAI1, STIM1, Sec22b, VAMP7; panel 4) with various functional implications. The ER plays instrumental roles in
secretory and transmembrane protein folding and quality control, protein and lipid trafficking, lipid metabolism, and Ca2+ homeostasis, all of
these processes being mediated by a diverse series of ER resident proteins (schematically depicted in panels 1 and 5).
organelles exerts its multifaceted roles in the function- ER [16] where they are exposed to an environment
ality of the cell as it is discussed in the next sections. abundant in chaperones and foldases that facilitate their
folding, assembly and post-translational modification
before they are exported from the ER [16]. Protein pro-
ER functions
cessing within the ER includes signal sequence cleavage,
The ER is involved in many different cellular func- N-linked glycosylation, formation, isomerization or
tions. It acts as a protein synthesis factory, contributes reduction of disulfide bonds [catalysed by protein disul-
to the storage and regulation of calcium, to the synthe- fide isomerases (PDIs), oxidoreductases], isomerization
sis and storage of lipids, and to glucose metabolism of proline or lipid conjugation, all of which ultimately
[3]. These diverse functions indicate a pivotal role for result in a properly folded conformation [16–19]. Mis-
the ER as a dynamic ‘nutrient sensing’ organelle that folded proteins are potentially detrimental to cell func-
coordinates energetic fluctuations with metabolic tion and are therefore tightly controlled. Although
reprogramming responses, regulating metabolism and protein misfolding takes place continually, it can be
cell fate decisions (Fig. 1). exacerbated during adverse intrinsic and environmental
conditions. The ER has developed quality control sys-
tems to ensure that there are additional opportunities to
Protein folding and quality control
correct misfolded proteins or, if terminally misfolded, to
The ER is involved in secretory and transmembrane be disposed of by the cell. Terminally misfolded secre-
protein synthesis, folding, maturation, quality control tory proteins are eliminated by a process called ER-
and degradation, and ensures that only properly folded associated degradation (ERAD) [20]. Proteins are first
proteins are delivered to their site of action [15]. About recognized by an ER resident luminal and transmem-
30% of all proteins are cotranslationally targeted to the brane protein machinery, then retrotranslocated into
the cytosol by a channel named dislocon [21] and the Ca2+ homeostasis
cytosolic AAA+ ATPase p97 [22], deglycosylated by N-
Ca2+ is involved as a secondary messenger in many
glycanase (NGLY1; [23]) and targeted for degradation
intracellular and extracellular signalling networks,
via the ubiquitin–proteasome pathway [20,24,25]
playing an essential role in gene expression, protein
(Fig. 1).
synthesis and trafficking, cell proliferation, differentia-
tion, metabolism or apoptosis [33]. ER, as the main
Lipid synthesis cellular compartment for Ca2+ storage, plays a pivotal
role in the regulation of Ca2+ levels and reciprocally
The ER also plays essential roles in membrane produc-
many ER functions are controlled in a Ca2+-depen-
tion, lipid droplet/vesicle formation and fat accumula-
dent way, thereby regulating the calcium homeostasis
tion for energy storage. Lipid synthesis is localized at
of the whole cell [34]. Consequently, both ER and
membrane interfaces and organelle contact sites, and
cytosolic Ca2+ concentrations need to be highly spa-
the lipid droplets/vesicles are exported in a regulated
tiotemporally regulated in order for the ER to main-
fashion. The ER dynamically changes its membrane
tain a much increased physiological intraluminal Ca2+
structure to adapt to the changing cellular lipid con-
concentration and oxidizing redox potential than the
centrations. The ER contains the sterol regulatory ele-
cytoplasm. To modulate these levels, the ER employs
ment-binding protein family of cholesterol sensors
a number of mechanisms that control Ca2+ concentra-
ensuring cholesterol homeostasis [26]. This compart-
tion on both sides of the membrane: (a) ER membrane
ment also hosts enzymes catalysing the synthesis of cell
ATP-dependent Ca2+ pumps for cytosol-to-lumen
membrane lipid components, namely sterols, sphin-
transport; (b) ER luminal Ca2+-binding chaperones
golipids and phospholipids [27]. The synthesis of those
for sequestering free Ca2+; and (c) ER membrane
lipids from fatty acyl-CoA and diacylglycerols takes
channels for the regulated release of Ca2+ into the
place at the ER membrane [28], which also hosts 3-
cytosol. These mechanisms are facilitated by a tight
hydroxy-3-methyl-glutaryl-coenzyme A reductase, the
communication between the ER and other organelles,
rate-limiting enzyme of the mevalonate/isoprenoid
such as the PM and the mitochondria, thereby sup-
pathway that produces sterol and isoprenoid precur-
porting the cell needs.
sors [29]. Precursors made by ER membrane-localized
Traditionally thought as a site of protein synthesis,
enzymes are subsequently converted into structural
recent evidence has established the involvement of the
lipids, sterols, steroid hormones, bile acids, dolichols,
ER in many different cellular functions: from novel
prenyl donors and a myriad of isoprenoid species with
roles in lipid metabolism to connections with
key functions for cell metabolism. Interestingly,
cytoskeletal structures or roles in cytoplasmic stream-
MAMs have been identified as a privileged site of sph-
ing, our view of the ER keeps rapidly expanding, plac-
ingolipid synthesis [30] (Fig. 1).
ing it increasingly as a key organelle governing the
whole cellular metabolism.
ER export
Most of the proteins and lipids synthesized in the ER Perturbing ER functions
must be transported to other cellular structures,
Conditions that disrupt ER homeostasis create a cellu-
which occurs mostly through the secretory pathway.
lar state commonly referred to as ‘ER stress’. The cel-
To maintain the constant anabolic flux, export needs
lular response to ER stress involves the activation of
to be tightly regulated, and defects in secretion can
adaptive mechanisms to overcome stress and restore
lead to serious structural and functional consequences
ER homeostasis. This response is dependent on the
for the ER. Central to this export process is the gen-
perturbing agent/condition and the intensity/duration
eration of ER COPII transport vesicles, named after
of the stress [35].
the family of proteins that shapes and coats them
[31]. In addition to COPII vesicle transport, several
other mechanisms of lipid export have been Intrinsic ER perturbations
described. A variety of lipids can be transported by
nonvesicular mechanisms; for example, large lipopro- Cell autonomous mechanisms can lead to ER pertur-
tein cargo has been shown to be exported out of the bation and examples of this can be seen in several dis-
ER in another type of vesicle termed prechylomicron eases, including cancer, neurodegenerative diseases and
transport vesicles [32] or to accumulate in lipid dro- diabetes. The hallmarks of cancer such as genetic
plets (Fig. 1). instability and mutations [36] can result in constitutive
activation of ER stress response pathways leading to whereas dithiothreitol inhibits protein disulfide bond
cell growth, proliferation, differentiation and migra- formation[52]. Alternatively, Brefeldin A impairs ER-
tion. In addition, the uncontrolled, rapid growth of to-Golgi trafficking, thus causing a rapid and reversi-
cancer cells requires high protein production rates with ble inhibition of protein secretion [53]. Targeting the
a consequent impact on ER systems [37]. Many can- Sarco/ER Ca2+-ATPase (SERCA) with compounds,
cers have a high mutation load which results in an such as thapsigargin and cyclopiazonic acid [54,55],
intrinsically higher level of ER stress. For example, induces ER stress by reducing ER Ca2+ concentration
melanoma has the highest mutation burden of any and impairing protein folding capacity.
cancer and the sheer numbers of mutated proteins are
a source of intrinsically higher ER stress levels. In
Exposure to enhancers of ER homeostasis
chronic myeloid leukaemia, the fusion protein pro-
duced the Philadelphia chromosome, BCR-ABL1, is a Conversely, other molecules have been found that can
constitutively active oncoprotein that enhances cell alleviate ER stress. These include small molecules, pep-
proliferation and interferes with Ca2+-dependent tides and proteostasis regulators. The frequently used
apoptotic response [38]. In addition, mutation-driven 4-phenylbutyric acid (4-PBA) reduces the accumulation
ER stress can also induce senescence that contributes of misfolded proteins in the ER [56]. Tauroursodeoxy-
to chemoresistance [39]. ER stress has also been linked cholic acid (TUDCA) is an endogenous bile acid able
to several neurodegenerative diseases. For example, to resolve ER stress in islet cells [57]. TUDCA is the
mutations in the ER resident vesicle-associated mem- taurine conjugate of ursodeoxycholic acid (UDCA), an
brane protein-associated protein B in familial amy- FDA-approved drug for primary biliary cirrhosis that
otrophic lateral sclerosis (ALS) are linked to induction is also able to alleviate ER stress [58]. The precise
of motor neuron death mediated by the alteration of mode of action of such proteostasis modulators still
ER stress signalling [40,41]. On the other hand, secre- remains elusive.
tory cells such as pancreatic b cells have a highly
developed ER to manage insulin production and
Temperature
release in response to increases in blood glucose. The
C96Y insulin variant leads to its impaired biogenesis Body temperature is crucial for the viability of meta-
and ER accumulation in the Akita mouse. As the ER zoans; normal mammalian physiological temperatures
cannot cope with the mutation induced stress, beta are 36–37 °C. Deviations from this range can disrupt
cells die and type 1 diabetes develops [42,43]. Insulin cellular homeostasis causing protein denaturation and/
mutation-related ER stress was also reported in neona- or aggregation [59]. Moreover, an acute increase in
tal diabetes [44,45]. temperature, known as heat shock, causes the frag-
mentation of both ER and Golgi [59]. Heat precondi-
tioning at mildly elevated temperatures (up to 40 °C)
Extrinsic perturbations in mammalian cellular and animal models has been
shown to lead to the development of thermotolerance,
Microenvironmental stress
which is associated with an increase in the expression
In tumours, the ER stress observed in rapidly prolifer- of several heat shock proteins and ER stress markers
ating cells is compounded by the fact that increased [60,61]. In addition, moderate hypothermia (28 °C)
proliferation eventually depletes the microenvironment induces mild ER stress in human pluripotent stem
of nutrients and oxygen, causing local microenviron- cells, the activation of which may be sufficient to pro-
mental stress and resulting in hypoxia, starvation and tect against severe stress through an effect known as
acidosis, all of which cause ER stress and perturb pro- ER hormesis [62,63].
tein, and possibly lipid synthesis [46]. Nutrient depri-
vation, and particularly glucose starvation, at least in
Reactive oxygen species production and other
part, promotes ER stress by impairing glycosylation.
perturbations
Several external agents can induce intracellular reactive
Exposure to ER stressors
oxygen species (ROS) production, and when ROS pro-
Several small molecules that induce ER stress through duction exceeds the antioxidant capacity oxidative
a variety of mechanisms have been identified [47,48]. stress negatively affects protein synthesis and ER
Stressors such as tunicamycin [49,50], or 2-deoxyglu- homeostasis [64]. ROS, including free radicals, are gen-
cose [51] target the N-linked glycosylation of proteins, erated by the UPR-regulated oxidative folding
machinery in the ER [65] and in the mitochondria [66]. BiP, IRE1 and PERK homodimerize or oligomerize
In this context, increased mitochondrial respiration and trans-autophosphorylate to activate their down-
and biogenesis promotes survival during ER stress stream pathways [72]. In contrast, BiP dissociation
through a reduction of ROS [67]. The ER provides an from AFT6 reveals an ER export motif [73] which facil-
oxidizing environment to facilitate disulfide bond for- itates its translocation to the Golgi apparatus [77]. This
mation and this process is believed to contribute to as ‘competition model’ of UPR activation assumes that
much as 25% of the overall ROS generated [68,69]. BiP acts as a negative regulator of UPR signalling.
The interconnection between the ER and ROS is medi- However, other BiP-dependent or independent models
ated by signalling pathways which involve glutathione have been proposed (reviewed in [78]; Fig. 2).
(GSH)/glutathione disulfide, NADPH oxidase 4,
NADPH-P450 reductase, Ca2+, ER oxidoreductin 1
IRE1 signalling
(ERO1) and PDI [70]. The latter, in particular, has
been found upregulated in the central nervous system In humans, there are two paralogues of IRE1 (IRE1a
of Alzheimer’s disease patients thus highlighting the and b), encoded by endoplasmic reticulum to nucleus
relevance of these pathways in neurodegenerative dis- signalling 1 and 2 (ERN1 and ERN2), respectively
ease [71]. Overall, from the sections above it is appar- [79–81]. Both human IRE1 isoforms share significant
ent that directly or indirectly impaired ER function sequence homology (39%) [20]. IRE1a (referred to
contributes to disease development and treatment IRE1 hereafter) is ubiquitously expressed; however,
resistance. inositol-requiring enzyme 1 b (IRE1b) expression is
restricted mainly to the gastrointestinal tract and the
pulmonary mucosal epithelium [82,83]. Ern1 knockout
ER stress consequences
(KO) in mice is embryonic lethal due to growth retar-
In response to ER stress, cells trigger an adaptive sig- dation and defects in liver organogenesis and placen-
nalling pathway called the unfolded protein response tal development [84] while Ern2 KO mice develop
(UPR), which acts to help cells to cope with the stress colitis of increased severity and shorter latency [82]
by attenuating protein synthesis, clearing the unfolded/ but are otherwise histologically indistinguishable from
misfolded proteins and increasing the capacity of the the Ern2WT mice. BiP dissociation, caused by accu-
ER to fold proteins. mulating unfolded proteins, triggers IRE1 oligomer-
ization and activation of its cytosolic kinase domain.
The oligomers position in close proximity, in a face-
The UPR
to-face orientation, enabling trans-autophosphoryla-
The UPR is a cellular stress response originating in the tion. This face-to-face configuration is adopted by
ER and is predominantly controlled by three major sen- both human and murine IRE1 [85,86]. Phosphoryla-
sors: inositol requiring enzyme 1 (IRE1), protein kinase tion in the activation loop of the kinase domain,
RNA-activated (PKR)-like ER kinase (PERK) and specifically at Ser724, Ser726 and Ser729, is not only
activating transcription factor 6 (ATF6). The ER lumi- necessary to activate its cytosolic RNase domain [87]
nal domains of all three ER stress sensors are normally but is also required to initiate recruitment of tumour
bound by the ER resident chaperone, heat shock pro- necrosis factor receptor-associated factor 2 (TRAF2)
tein A5 [heat shock protein family A (Hsp70) member and JNK pathway signalling [88]. The IRE1 cytosolic
5, also known as glucose-regulated protein 78 (GRP78) domain, which is highly homologous with RNase L
and binding immunoglobulin protein (gene GRP78) [89], induces a selective cleavage of dual stem loops
(BiP)], keeping them in an inactive state [72,73]. Accu- within the X-box binding protein 1 (XBP1) mRNA
mulating misfolded proteins in the ER lumen engage [79,90,91]. Therefore, IRE1, in a spliceosome indepen-
BiP thus releasing the three sensors. A FRET UPR dent-manner, but together with the tRNA ligase
induction assay, developed to quantify the association RNA 20 ,30 -cyclic phosphate and 50 -OH ligase [92–97],
and dissociation of the IRE1 luminal domain from BiP catalyses the splicing of a 26 nucleotide intron from
upon ER stress [74], demonstrated that the ER luminal human XBP1 mRNA to produce spliced isoform of
co-chaperone ERdj4/DNAJB9 represses IRE1 by pro- XBP1 (XBP1s) [90,91]. XBP1s is a basic leucine zip-
moting a complex between BiP and the luminal stress- per (bZIP) transcription factor [98–100] and the
sensing domain of IRE1a [75]. Moreover, it has unspliced isoform of XBP1 (XBP1u) is unable to acti-
recently been reported that another ER luminal chaper- vate gene expression due to lack of a transactivation
one, Hsp47, displaces BiP from the IRE1 UPRosome domain [91]. The N-terminal region of XBP1u con-
to promote its oligomerization [76]. Once released from tains a basic region and a leucine zipper domain
Fig. 2. Signalling the UPR and downstream pathways. The 3ER stress sensors (PERK, IRE1, ATF6) upon release from BiP, PDIA5, 6 initiate
signalling cascades through transcription factor production (ATF4, XBP1s, ATF6f) and associated processes such as RIDD, NFjB activation
and ERAD to address the misfolded protein load on the ER. By modulating transcriptional output and translational demand the UPR
attempts to re-establish ER protein folding homeostasis and promote cell survival. If ER stress cannot be resolved then mechanisms are
triggered to promote cell death.
involved in dimerization and DNA binding T (threonine) motif which destabilizes proteins (ubiq-
[91,98,100,101]. The XBP1u C-terminal region con- uitin-dependent proteolysis) and contributes to its
tains a P (proline), E (glutamic acid), S (serine) and short half-life [98,101–103]. The N-terminal region
also contains two other domains: a hydrophobic progressively with the severity of ER stress. However,
region that targets XBP1u to the ER membrane and this hypothesis needs further experimental validation.
a domain that promotes efficient XBP1 splicing [104– Interestingly, IRE1b was found to selectively induce
106] and cleavage [103] by pausing XBP1 translation. translational repression through the 28S ribosomal
IRE1-mediated splicing of XBP1 mRNA results in an RNA cleavage [81] demonstrating that IRE1a and
open reading frame-shift inducing the expression of a IRE1b display differential activities [148]. Characteriz-
transcriptionally active and BP1s [90,91,101]. XBP1u ing RIDD activity, particularly in vivo, has proven dif-
has been reported to negatively regulate XBP1s tran- ficult due to the complex challenge of separating the
scriptional activity as well as to promote the recruit- RIDD activity from the XBP1 splicing activity of
ment of its own mRNA to the ER membrane IRE1. In addition, basal RIDD can only target specific
through the partial translation of its N-terminal mRNA substrates, as full activation and subsequent
region [107,108]. XBP1s directs the transcription of a targeting of further transcripts requires strong ER
wide range of targets including the expression of stress stimuli (Fig. 2).
chaperones, foldases and components of the ERAD
pathway, in order to relieve ER stress and restore
PERK signalling
homeostasis [109,110]. However, XBP1s can also par-
ticipate in the regulation of numerous metabolic path- PERK was identified in rat pancreatic islets as a ser-
ways such as lipid biosynthesis [111–113], glucose ine/threonine kinase and, similar to PKR, heme regu-
metabolism [114–118], insulin signalling [117,119,120], lated initiation factor 2 alpha kinase and general
redox metabolism [121], DNA repair [122] and it control nonderepressible 2, can phosphorylate eIF2a
influences cell fate including cell survival [123], cell [149,150]. PERK is ubiquitously expressed in the body
differentiation [124–128] and development [126,129– [149] and has an ER luminal domain as well as a cyto-
131]. Although there is strong evidence pointing to a plasmic kinase domain [150]. BiP detachment from the
key role for XBP1 in multiple cellular functions, the ER luminal domain leads to oligomerization [72],
exact mechanisms by which XBP1 mediates gene trans-autophosphorylation and activation of PERK
transactivation are still elusive. Indeed, in addition to [151]. Active PERK phosphorylates eIF2a on serine 51
the known interaction of the XBP1s transactivation [150]. eIF2a is a subunit of the eIF2 heterotrimer
domain with RNA polymerase II, other mechanisms [152,153] which regulates the first step of protein syn-
could exist. For example, XBP1 can physically inter- thesis initiation by promoting the binding of the initia-
act with many other transcription factors such as AP- tor tRNA to 40S ribosomal subunits [154]. However,
1 transcription factor subunit [132], oestrogen recep- eIF2a phosphorylation by PERK inhibits eukaryotic
tor a (ERa) [133], GLI-family zinc finger 1 [134], translation initiation factor 2B (eIF2B) activity and
SSX family member 4 [134], forkhead box O1 [114], thereby downregulates protein synthesis [155]. Block-
ATF6 [135], cAMP response element-binding protein ing translation during ER stress consequently reduces
(CREB)/ATF [135] and hypoxia inducible factor 1 the protein load on the ER folding machinery [156].
alpha subunit [136] (Fig. 2). Remarkably, some transcripts are translated more
The RNase activity of IRE1 can also efficiently tar- efficiently during PERK-dependent global repression
get other transcripts through a mechanism called regu- of translation initiation. The ubiquitously expressed
lated IRE1-dependent decay (RIDD) [137]. Analysis of activating transcription factor 4 (ATF4) [157], whose
the in vitro RNase activity of wild-type (WT) vs transcript contains short upstream open reading
mutant IRE1 led to the discovery of a broad range of frames (uORFs) [158], is normally inefficiently trans-
other IRE1 substrates [138,139] and, interestingly, it lated from the protein-coding AUG [159]. However,
was noted that IRE1 can also degrade its own mRNA attenuation of translation from uORFs shifts transla-
[140]. RIDD is a conserved mechanism in eukaryotes tion initiation towards the protein coding AUG,
[137,141–145] by which IRE1 cleaves transcripts con- resulting in more efficient synthesis of ATF4 [158].
taining the consensus sequence (CUGCAG) accompa- ATF4 can then bind to the C/EBP-ATF site in the
nied by a stem-loop structure [142,146]. The cleaved promoter of CAAT/enhancer-binding protein (C/EBP)
RNA fragments are subsequently rapidly degraded by homologous protein (CHOP)/GADD153 [160] and
cellular exoribonucleases [141,147]. RIDD is required induce its expression [158]. ATF4 and CHOP directly
for the maintenance of ER homeostasis by reducing induce genes involved in protein synthesis and the
ER client protein load through mRNA degradation UPR [161], but conditions under which ATF4 and
[137,141,142]. Recently, it has been proposed that CHOP increase protein synthesis can result in ATP
there is basal activity of RIDD [138] which increases depletion, oxidative stress and cell death [162]. eIF2a
phosphorylation (p-eIF2a) can also directly enhance transcription factor 2 [161] and XBP1 [71], and various
the translation of CHOP [163,164] and other proteins other transcription factors such as serum response fac-
involved in the ER stress response, as reviewed in tor [181], components of the nuclear transcription factor
[165]. For example, growth arrest and DNA-damage- Y (NF-Y) complex [159,162,163], yin yang 1 [163,164]
inducible 34 (GADD34) [166,167] is positively regu- and general transcription factor I [165]. Converging
lated by eIF2a phosphorylation [168] and likewise with IRE1 and PERK signalling cascades, ATF6 can
transcriptionally induced by ATF4 [169] and CHOP also induce the expression of XBP1 and CHOP to
[170]. Interestingly, GADD34 interacts with the cat- enhance UPR signalling [30,166,167]. However, ATF6
alytic subunit of type 1 protein serine/threonine phos- is not the only ER-resident bZIP transcription factor.
phatase (PP1) [171], which dephosphorylates eIF2a At least five other tissue-specific bZIPs, named Luman,
thereby creating a negative feedback loop that antago- cAMP responsive element-binding protein 3 like 1
nizes p-eIF2a-dependent translation inhibition and (OASIS), cAMP responsive element-binding protein 3
restores protein synthesis [169,170,172]. The transla- like 2 (BBF2H7), CREB3L3 and CREB, reviewed in
tional arrest induced by p-eIF2a reduces protein load [183], are involved in ER stress signalling (Fig. 2), high-
in ER lumen and conserves nutrients, while ATF4 dri- lighting the regulatory complexity this branch of the ER
ven expression of adaptive genes involved in amino stress response is subjected to at the organismal level.
acid transport and metabolism, protection from oxida-
tive stress, protein homeostasis and autophagy
Noncoding RNAs
together help the cell to cope with ER stress [173,174].
However, sustained stress changes the adaptive Noncoding RNAs are connected to the three UPR sen-
response to a prodeath response and ultimately, the sors with effects on both physiological and pathological
phosphorylation status of eIF2a appears to codeter- conditions [184]. These RNA species mostly include
mine the balance between prosurvival or prodeath sig- microRNAs (miRNAs) and also long noncoding RNAs
nalling [175,176]. This is accomplished by the above (lncRNAs). This additional level of regulation works in
mentioned delayed feedback through which the inter- fact in a bidirectional manner. This means that either
play of GADD34, ATF4 and CHOP results in the the UPR sensors themselves or their downstream com-
activation of genes involved in cell death, cell-cycle ponents can also modulate their expression levels. A
arrest and senescence [177–180] (Fig. 2). certain number of miRNAs have been so far recognized
to regulate IRE1, which in turn regulates miRNAs
through XBP1s at a transcriptional level and through
ATF6 signalling
RIDD activity via degradation. One miRNA regulates
The transcription factor ATF6, which belongs to an PERK expression, while this in turn regulates miRNAs
extensive family of leucine zipper proteins [8], is encoded through its downstream targets. ATF6 is also modu-
in humans by two different genes: ATF6A for ATF6a lated by miRNAs, but only one miRNA has been
[181] and ATF6B for ATF6b [153]. After its activation found under its direct effect. Upstream of IRE1, PERK
in the ER and export to the Golgi, it is cleaved by the and ATF6, the BiP chaperone is also regulated by miR-
two Golgi-resident proteases membrane bound tran- NAs but does not control any. In addition to miRNAs,
scription factor peptidase, site 1 (MBTPS1) and lncRNAs exhibit a similar role regarding the regulation
MBTPS1, releasing a fragment of ~ 400 amino acids of UPR factors and vice versa. Their levels change in
corresponding to ATF6 cytosolic N-terminal portion accordance to the cell stress status and depending on
(ATF6f). ATF6f comprises a transcriptional activation the pathophysiological context lead to distinct cell
domain (TAD), a bZIP domain, a DNA-binding fates. This interconnection between noncoding RNAs
domain and nuclear localization signals. In the nucleus, and the UPR may contribute to a more complex net-
ATF6f induces UPR gene expression [73,182]. Although work but at the same time reveals the existence of fine-
the two ATF6 paralogs share high homology [153], tuning mechanisms governing ER stress responses and
ATF6b is a very poor activator of UPR genes due to the their effects in cell homeostasis (described in [184]).
absence of eight important amino acids in the TAD
domain [157]. Indeed, it rather seems to function as an
inhibitor by forming heterodimers with ATF6a [10,158]. Proximal impact of UPR activation
Interestingly, ATF6 can modulate gene expression by
Transcriptional programmes
interacting with other bZIPs, such as CREB [159],
cAMP responsive element-binding protein 3 like 3 Each branch of the UPR pathway culminates in tran-
(CREB3L3) [160], sterol regulatory element-binding scriptional regulation and, together the UPR’s major
transcription factors, ATF6f, XBP1s and ATF4, stim- to limit protein build-up [187,191]. Autophagy is a
ulate many adaptive responses to restore ER function pathway involved in the degradation of bulk compo-
and maintain cell survival [35]. They regulate genes nents such as cellular macromolecules and organelles.
encoding ER chaperones, ERAD factors, amino acid It involves target recognition and selectivity, sequester-
transport and metabolism proteins, phospholipid ing targets within autophagosomes, followed by the
biosynthesis enzymes, and numerous others [185]. In fusion of the autophagosome with the lysosome, where
particular, the IRE1–XBP1 pathway is involved in the targets are then degraded by lysosomal hydrolases
induction of ER chaperones and capacity control of [187,192]. The direct link between ER stress and
ERAD [186] as well as promoting cytoprotection [187] autophagy has been established in both Saccha-
and cleaving miRNAs that regulate the cell death- romyces cerevisiae and mammalian cells, where autop-
inducing caspases [188]. ATF6f translocates to the hagy plays a solely cytoprotective role. The PERK
nucleus where it activate genes involved in protein (eIF2a) and IRE1 (TRAF2/JNK) branches of the
folding, processing, and degradation [185]. ATF4, acti- UPR have been implicated in ER stress-induced
vated downstream of PERK and p-eIF2a, increases autophagy in mammalian systems to avoid accumula-
the transcription of many genes that promote survival tion of lethal disease-associated protein variants [192].
under ER stress. Some of these prosurvival genes IRE1–JNK signalling activates Beclin 1, a key player
include genes that are involved in redox balance, and regulator of autophagy, via the phosphorylation
amino acid metabolism, protein folding and autophagy of Bcl-2 and the subsequent dissociation from Beclin
[189]. 1. This then leads to the activation of ATG proteins
required for the formation of the autophagolysosome
[193]. Overall, these mechanisms decrease the build-up
Translational programmes
of improperly folded proteins in the ER thus allowing
Translation is directly impacted by UPR activation adaptive and repair mechanisms to re-establish home-
under ER stress conditions, particularly by PERK as ostasis. As the amounts of improperly folded proteins
described above. It also affects the expression of sev- decrease, the UPR switches off. However, the molecu-
eral miRNAs, which may further contribute to transla- lar details of UPR attenuation still remain to be fur-
tion attenuation or protein synthesis [35]. It has been ther elucidated.
shown that ER stress can regulate the execution phase Overall, the three mechanisms describe above
of apoptosis by causing the transient induction of inhi- decrease the build-up of proteins in the ER which
bitor of apoptosis proteins (IAPs). Several papers have allows adaptive and repair mechanisms to re-establish
reported that cIAP1, cIAP2 and XIAP are induced by homeostasis. As the amounts of improperly folded
ER stress, and that this induction is important for cell proteins decrease, the UPR switches off. However, the
survival, as it delays the onset of caspase activation molecular details of UPR attenuation remain to be
and apoptosis. PERK induction of cIAPs and the further elucidated.
transient activity of PI3K–AKT signalling suggest that
PERK not only allows adaptation to ER stress, but it
Regulation of MAMs
also actively inhibits the ER stress-induced apoptotic
programme [190]. Mitochondria-associated membranes (MAMs), which
are mainly responsible for Ca2+ homeostasis mainte-
nance as well as lipid transport, mediate the interaction
Protein degradation
between the ER and mitochondria thereby controlling
There are two main protein degradation pathways mitochondrial metabolism and apoptosis [194]. MAMs
activated by components of the UPR following ER contain many proteins and transporters which mediate
stress: ubiquitin–proteasome-mediated degradation via mitochondrial clustering and fusion, such as the dyna-
ERAD and lysosome-mediated protein degradation via min-like GTPase mitofusin-2 (MFN2) [195]. MFN2
autophagy. ERAD is responsible for removing mis- interacts with PERK, serving as an upstream modula-
folded proteins from the ER and several genes tor and thereby regulating mitochondrial morphology
involved in ERAD are upregulated by ATF6f and and function as well as the induction of apoptosis
XBP1s [185]. ERAD involves the retrotranslocation of [196]. Furthermore, the cytosolic domain of PERK
misfolded proteins from the ER into the cytosol where serves as an ER-mitochondria tether, thus facilitating
they are degraded by the proteasome (see above) [187]. ROS-induced cell death [197].The sigma 1 receptor
When accumulation of misfolded proteins overwhelms (Sig-1R) is located in the MAMs and forms a complex
ERAD, autophagy is induced as a secondary response with BiP. Recent studies show that S1R stabilizes IRE1
at the MAMs upon ER stress, promoting its dimeriza- on ATF4 to induce the expression of cytoprotective
tion and conformational change, and prolonging the genes [174]. Another pathway regulating energy meta-
activation of the IRE1–XBP1 signalling pathway bolism is the nutrient-sensing mammalian target of
through its long-lasting endoribonuclease activity. Fur- rapamycin (mTOR) signalling hub. mTOR is associ-
thermore, mitochondria-derived ROS stimulates IRE1 ated with the UPR through crosstalk with regulatory
activation at MAMs [198]. Another MAM component pathways (reviewed in [206]), and mTOR inhibitors
is Bax-inhibitor-1 (BI-1), regulating mitochondrial such as rapamycin lead to the activation of PERK
Ca2+ uptake and apoptosis. BI-1 is a negative regula- signalling, thus favouring cell viability [207]. PERK
tor of IRE1-XBP1 signalling and in BI-1 deficient cells can also regulate the PI3K–AKT–mTORC1 axis
there is IRE1 hyperactivation and increased levels of through the activation of AKT. Furthermore, it was
its downstream targets [199]. Apoptosis activation by observed that mTORC2 plays a role in the inhibition
the UPR results in mitochondrial membrane permeabi- of PERK through AKT activation [208]. Altogether
lization, with the resulting Ca2+ transfer potentially these data suggest that crosstalk between mTOR and
triggering mitochondrial cytochrome c release [200]. the UPR is complex and occurs through multiple
Less well understood are the interactions of the mito- pathways.
chondria with the ER during sublethal ER stress. The
latter results in more ER-mitochondria contacts than
Lipid metabolism
lethal levels of ER stress, allowing for transfer of Ca2+
and enhancement of ATP production through The UPR can also be activated by deregulated lipid
increased mitochondrial metabolism [201] (Fig. 1). metabolism. In this regard, the UPR has been shown
These evidences demonstrate the importance of the to be activated in cholesterol-loaded macrophages
ER-mitochondria communication in regulating the ER resulting in increased CHOP signalling and apoptosis
homeostasis and in coordinating the cellular response [209]. Notably, chronic ER stress leads to insulin
to ER stress, thereby restoring cellular homeostatic resistance and diabetes in obesity. This is caused by
condition or leading towards cell death. alterations in lipid composition which lead to inhibi-
tion of SERCA activity and hence ER stress [210].
On the other hand, the UPR is involved in systemic
Redox homeostasis
metabolic regulation. Disturbance of ER homeostasis
Oxidative stress can be induced through several mech- in the liver is involved in hepatic inflammation,
anisms and is critically controlled by the UPR. PERK steatosis and nonalcoholic fatty liver disease [211].
activity helps to maintain redox homeostasis through The PERK–eIF2a pathway has been reported to reg-
phosphorylation of NRF2 which functions as a tran- ulate lipogenesis and hepatic steatosis. Compromising
scription factor for the antioxidant response [202]. eIF2a phosphorylation in mice by overexpression of
ATF4 also regulates redox control and has been GADD34 results in reduced hepatosteatosis upon
shown to protect fibroblasts and hepatocytes from high-fat diet [212]. ATF4 the downstream effector of
oxidative stress [173], as well as ensuring that there is PERK–eIF2a pathway has also been suggested to
an adequate supply of amino acids for protein and regulate lipid metabolism in hepatocytes in response
GSH biosynthesis [203]. However, in neurons and to nutritional stimuli by regulating expression of
HEK293 cells ATF4 was shown to induce cell death in genes involved in fatty acid and lipid production
response to oxidative stress while CHOP was reported [213,214]. Furthermore, it has been demonstrated that
to induce ERO1-a, resulting in ER Ca2+ release and the IRE1–XBP1–PDI axis links ER homeostasis with
apoptosis in macrophages [204]. Direct interactions of VLDL production which plays an important role in
PDIs with ER stress sensors, protein S-nitrosylation dyslipidaemia [215]. In addition, XBP1 is required for
and ER Ca2+ efflux that is promoted by ROS con- the normal hepatic fatty acid synthesis and it was
tribute to redox homeostasis and by extension to the shown that selective XBP1 deletion in mice resulted
balance between prosurvival and prodeath UPR sig- in marked hypocholesterolaemia and hypotriglyceri-
nalling [205]. As such, these signalling loops are para- daemia [216]. These studies suggest that ER stress
mount to normal cellular function. and the UPR are involved in lipid metabolism.
Relieving ER stress ameliorates the disease state asso-
ciated with lipid metabolism alterations, suggesting
Global metabolic impact of the UPR
that targeting ER stress might serve as a therapeutic
It was recently shown that the UPR and mitochon- strategy for treating diseases associated with lipid
drial proteotoxic stress signalling pathways converge accumulation.
Glucose metabolism for the cell to regulate metabolism through regulating

mTOR signalling, lipid homeostasis as well as insulin
It has been suggested that in the liver the PERK–
signalling.
eIF2a pathway is responsible for disruption of insulin
signalling caused by intermittent hypoxia, though
IRE1–JNK pathways may still play a role [217]. Adi- Downstream impact of UPR activation
ponectin is widely regarded as a marker of functional
The activation of UPR leads to the modulation of
glucose metabolism and as a suppressor of metabolic
many cellular pathways, thereby influencing prosur-
dysfunctions. In hypoxic and ER-stressed adipocytes,
vival mechanisms as well as processes such as prolifer-
reduced adiponectin mRNA levels are observed due
ation, differentiation, metabolism and cell death.
to negative regulation by CHOP [218,219]. In b-cells,
it was shown that IRE1 is involved in insulin biosyn-
thesis after transient high glucose levels. However, UPR-associated cell death
chronic exposure to high glucose leads to full UPR
Following prolonged activation of the UPR, the cellu-
induction and insulin downregulation[220]. IRE1 sig-
lar response switches from prosurvival to prodeath.
nalling was shown to be involved in insulin resistance
Several types of cell death, including apoptosis, necro-
and obesity through JNK activation. In hepatocytes,
sis/necroptosis and autophagic cell death, can be
IRE1-dependent JNK activation leads (a) to insulin
induced following ER stress.
receptor substrate 1 (IRS1) tyrosine phosphorylation
(pY896) decrease and (b) to AKT activation leading
to an increase of IRS1 phosphorylation (pS307), con- Apoptosis
sequently blocking insulin signalling. A role for
XBP1 in the pancreas was demonstrated by the fact Unresolved ER stress can lead to the activation of
that b-cell-specific XBP1 mutant mice show hypergly- either the intrinsic (mitochondrial) or extrinsic [death
caemia and glucose intolerance due to decreased receptor (DR)] pathways of apoptosis. Both pathways
insulin release of b-cells [221]. ER stress-induced acti- trigger activation of caspase proteases that dismantle
vation of ATF6 in rat pancreatic beta cells exposed the cell, and all of the three branches of the UPR are
to high glucose, impairs insulin gene expression and involved in apoptosis. In the extrinsic pathway, the
glucose-stimulated insulin secretion. Interestingly, activation of DRs on the PM leads to the recruitment
knocking down expression of orphan nuclear receptor of caspases to the DRs and their proximity-induced
short heterodimer partner (SHP) previously reported trans-autoactivation. Intrinsic apoptosis involves the
to be involved in beta cell dysfunction by downregu- release of cytochrome c (along with other proapoptotic
lating expression of PDX-1 and RIPE3b1/MafA factors) from the mitochondria, which promotes the
partly mitigated this effect. However, it remains formation of a cytosolic protein complex to activate a
unclear how ATF6 induces expression of SHP and caspase cascade. This release is controlled by pro- and
whether ATF6 alone can directly regulate the expres- antiapoptotic members of the BCL-2 protein family.
sion of insulin, PDX-1 and RIPE3b1/MafA [222]. It In particular, the BH3-only members of the family
has been suggested that physiological impact of ER including PUMA, NOXA and BIM are pivotal com-
stress with respect to glucose metabolism depends ponents of ER stress-induced apoptosis [224], and cells
upon the availability of glucose. Indeed acute glucose deficient in BH3-only proteins are protected against
availability in beta cells leads to concerted efforts of ER stress-induced cell death [190]. ER stress leads to
each branch of UPR to supply insulin, while chronic transcriptional upregulation of these proapoptotic
glucose stimulation leads to depletion of insulin pro- molecules resulting in cytochrome c release. Both the
duction and beta cell mass due to apoptosis. More- IRE1 and PERK arms of the UPR have been linked
over, chronic fasting conditions in mice have shown to induction of apoptosis during ER stress. In particu-
that XBP1s directly activates the promoter of the lar, CHOP, a transcription factor that is downstream
master regulator of starvation response, PPARa of PERK, and a direct target of ATF4, has been
demonstrating a further link between the UPR and implicated in the regulation of apoptosis during ER
glucose and lipid metabolism [223]. Acquiring further stress. As discussed in section PERK signalling
knowledge on link between UPR and metabolic sen- CHOP-induced expression of GADD34 promotes
sor mechanisms will significantly expand the possibil- dephosphorylation of p-eIF2a reversing translational
ity of gaining beneficial metabolic output. Taken inhibition and allowing transcription of genes includ-
together this indicates that the UPR arms are critical ing apoptosis-related genes [172]. CHOP activates
transcription of BIM and PUMA, while it represses photodynamic therapy (reviewed in [237]), drives a
transcription of certain antiapoptotic BCL-2 family danger signalling module resulting in the surface expo-
members such as MCL-1 [225]. In addition, the ATF4/ sure of the ER luminal chaperone calreticulin and the
CHOP pathway can increase the expression of other exodus of other danger-associated molecular patterns,
proapoptotic genes, such as TRAIL-R1/DR4 and eliciting immunogenic cell death (reviewed in [238]).
TRAIL-R2/DR5 which promote extrinsic apoptosis
[180]. Apart from CHOP, p53 is also involved in the
Necroptosis
direct transcriptional upregulation of BH3‑ only pro-
teins during ER stress. However, the link between p53 Necroptosis, a programmed form of cell death, is
activation and ER stress is unclear [226]. dependent on the activation of receptor-interacting
Although IRE1–XBP1s signalling is mainly prosur- protein kinase 1 (RIPK1), RIPK3 and mixed lineage
vival, IRE1 can promote apoptosis. Activated IRE1 kinase domain-like (MLKL) protein and has been
can interact directly with TRAF2, leading to the acti- linked to ER stress. In an in vivo mouse model of
vation of apoptosis signal-regulating kinase 1 (ASK1) spinal cord injury, there is induction of necroptosis and
and its downstream targets c-Jun NH2-terminal kinase ER stress, with localization of MLKL and RIPK3 on
(JNK) and p38 MAPK [227,228]. Phosphorylation by the ER in necroptotic microglia/macrophages suggest-
JNK has been reported to regulate several BCL-2 fam- ing a link between necroptosis and ER stress in these
ily members, including the activation of proapoptotic cells [239]. Necroptosis is frequently activated down-
BID and BIM, and inhibition of antiapoptotic BCL-2, stream of TNFR1 when apoptosis is blocked [240].
BCL-XL and MCL-1 [229,230]. In addition, p38 This has been linked to ER stress-induced necroptosis
MAPK phosphorylates and activates CHOP, which whereby tunicamycin kills L929 murine fibrosarcoma
increases expression of BIM and DR5, thereby pro- cells by caspase-independent, death ligand-independent,
moting apoptosis [231,232]. In fact, cell death induc- TNFR1-mediated necroptosis [241].
tion in HeLa cells overexpressing CHOP is dependent
on its phosphorylation by p38 MAPK [233]. Interest-
Autophagic cell death
ingly, it was proposed that ER stress and MAPK sig-
nalling act in a positive feed-forward relationship, as Endoplasmic reticulum stress has also been connected
ER stress induces MAPK signalling which in turn to autophagic cell death. Autophagy not only pro-
increases ER stress [234]. IRE1 signalling may also motes cell survival, but can also mediate nonapoptotic
contribute to apoptosis induction through prolonged cell death under experimental conditions when apopto-
RIDD activity which degrades the mRNA of protein sis is blocked, or in response to treatments that specifi-
folding mediators [142]. cally trigger caspase-independent autophagic cell death
Interestingly, recent studies indicate a role for miR- [192]. IRE1a mediated TRAF2 and ASK1 recruitment,
NAs in the induction of apoptosis following prolonged and subsequent JNK activation mediates autophagy.
ER stress. For example, miRNA29a which is induced JNK-mediated phosphorylation of BCL-2 releases
during ER stress via ATF4 results in the downregula- Beclin-1 (while XBP1s also transcriptionally upregu-
tion of antiapoptotic Bcl-2 family protein Mcl-1, and lates its expression), which interacts with the ULK1
thus promotes apoptosis [235]. miRNA7 has also been complex to promote vesicle nucleation that leads to
linked with ER stress-induced apoptosis, where IRE1 the formation of the autophagosome [242]. Activated
reduces miRNA7 levels which results in the stability of PERK can induce autophagy through ATF4 by induc-
a membrane-spanning RING finger protein, RNF183. ing vesicle elongation while Ca2+ release from the ER
RNF183 has an E3 ligase domain that then causes the lumen through the IP3R can relieve mTOR inhibition
ubiquitination and subsequent degradation of the anti- on the ULK1 complex [187].
apoptotic member of the BCL-2 family BCL-XL. Fol-
lowing prolonged ER stress, increased expression of
UPR-associated morphological changes
RNF183 via IRE1 leads to increased apoptosis [236].
In the last decade, it also became clear that ER Endoplasmic reticulum stress causes morphological
stress can profoundly modify the immunological con- changes in cellular models. Experiments to date have
sequences of apoptotic cell death. Accumulating largely focused on the morphologies associated with
in vitro and in vivo evidence have highlighted that the apoptotic and autophagic cell death resulting from
activation of the PERK arm of ER stress evoked in UPR activation. UPR-regulated flattening and round-
response to selected of anticancer therapies (including ing of cells, indicative of cell death, has been observed
anthracyclines, oxaliplatin, radiation and in many model systems, with traditional caspase-
dependent apoptosis being responsible [200,243–248]. upregulating protein expression [260]. In ATF6/
These morphological changes can be reversed by phys- murine models subjected to intermittent water depriva-
iological and pharmacological ER stress relief tion, similar downstream effects were observed, but
[247,249]. Both IRE1 and PERK arms of the UPR signalling pathways were not investigated [261]. ER
have been implicated in the observed changes stress-inducing agents palmitate and oxysterol 27-
[193,243,244,247,249–251]. As described above, pro- hydroxycholesterol both result in a reduction in leptin
grammed cell death and its associated morphological (a long-term mediator of energy balance) expression
changes have become a focal and much researched and extracellular concentrations. This has been attribu-
outcome of the use of UPR-inducing cytotoxic agents. ted, by using ChIP analysis and siRNA knockdowns,
An intensively studied consequence of ER stress is to the fact that the PERK downstream target CHOP
the epithelial to mesenchymal transition (EMT) and its negatively regulates C/EBPa, transcriptionally down-
role in cancer invasion and metastasis. EMT is an regulating its translation and release [262,263]. UPR
essential component of tissue repair following wound- activation has been implicated in the hypothalamic
ing, allowing for the migration of new healthy cells and brown adipose tissue response to thyroid hormone
into any lesions that have occurred. Morphological triiodothyronine (T3). Elevated T3 levels induce the
changes indicative of EMT have been observed in mul- UPR downstream of AMPK in the ventromedial
tiple cell models under physiologically relevant stress nucleus of the hypothalamus, resulting in decreased
(e.g. hypoxia) and pharmacological induction of ER ceramide levels. JNK1 KO revealed that it acts down-
stress [252–255]. The IRE1–XBP1 pathway has been stream of this AMPK-dependent activation, possibly
reported to negatively regulate the traditional epithelial as a target of IRE1 but to our knowledge no studies
marker E-cadherin, while positively regulating the mes- have yet confirmed this [264]. In response to ER stress
enchymal marker N-cadherin in models of colorectal, in hepatocytes, CREBH is exported from the ER and
breast and pulmonary fibrosis [254,256,257]. Breast cleaved in the Golgi apparatus. The CREBH cytosolic
cancer and pulmonary fibrosis models showed an fragment binds to the promoter region of hepcidin and
IRE1–XBP1-dependent regulation of mesenchymal transcriptionally upregulates its production [265].
promoting transcription factor SNAIL that is responsi- These examples of UPR-regulated hormone produc-
ble for EMT [254,256]. Human mammary epithelial tion and release give scope for further investigation
cells undergo EMT in response to PERK activation, into the longer term, system wide effects of UPR sig-
and PERK-mediated phosphorylation of eIF2a is nalling outside of the current focuses on cytotoxicity
required for invasion and metastasis [258]. Other ER and acute diseases.
stress-regulated pathways have been proposed to act in
the EMT in cellular models, including autophagy and
Physiological ER stress signalling
activation of c-SRC kinase in tubular epithelial cells
[259] and the compensatory activation of the NRF-2/ It has been established that ER stress signalling is
HO-1 antioxidative stress response pathway in HT-29 important in interorganelle and intercellular interac-
and DLD-1 colon cancer cells [252]. Therefore, UPR tions. It therefore comes as no surprise that it forms a
signalling pathways appear to induce morphological significant network of interactions upon which normal
changes indicative of EMT. These data have generated physiology is based. This is not only the case in
interest in the field of cancer research where the phar- humans, but is also conserved throughout species and
macological inhibition of UPR components might be has been an important fact in the design of experimen-
used to reduce tumour invasiveness and metastasis. tal model organisms to further study ER stress sig-
nalling and it role in physiology and disease.
Hormone production
Embryology and development
The tissues and cells of the endocrine system responsi-
ble for hormone production and extracellular sig- The UPR as the major conduit of ER stress regulation
nalling often have a high protein load, resulting in ER has been extensively studied in developmental biology
stress and activation of the UPR. OASIS (CREB3L1) in the majority of organisms commonly used in transla-
and ATF6a have been shown to regulate arginine tional research. The use of multiple models has been
vasopressin (AVP), a potent vasoconstrictor, in murine important in discerning the variable ER stress signalling
and rat models [260,261]. Upon dehydration or salt between species, as demonstrated by the discovery that
loading in rat models, cleaved active OASIS is protein quality control in mammals is critically depen-
observed binding the AVP promoter region, directly dent on ATF6 while the major player in
Caenorhabditis elegans and Drosophila melanogaster is development, making ER stress signalling a key regula-
IRE1 [182,266]. Mammalian and other embryos tor in the earliest stages of life in all organisms [277].
implanted in vitro or naturally, undergo a multitude of
physical, biochemical and cellular stresses involving epi-
Growth and differentiation
genetic changes as well as a disproportional increase in
protein synthesis load that affect cell differentiation, Many cell types experience a high protein load during
proliferation and growth.[267]. In zebrafish, transgenic various stages of differentiation and maturation, result-
models have been generated to monitor XBP1 splicing ing in ER stress. In several cases, morphological
during development and implantation, showing that changes required for the final function of the cell would
maternal XBP1s is active in oocytes, fertilized eggs and not be possible without transient activation of the
early stage embryos, presenting a potential model for UPR’s cytoprotective mechanisms. Deletion of PERK
study of the impact of water pollutants on embryogene- in murine models results in loss of pancreatic b cell
sis [268]. It was recently shown that in medaka fish the architecture but not in cell death, and was accompa-
JNK and RIDD pathways are dispensable for growth, nied by an increase in b cell proliferation. This mor-
with development solely dependent on the XBP1 arm phological change results in a diabetes mellitus-like
of IRE1 signalling, thereby supporting the hypothesis pathology and is not a result of increased cell death as
that XBP1 and RIDD may be differentially utilized in previously proposed [278]. Various haematopoietic lin-
development and homeostasis [269]. In C. elegans it has eages require the activation of the UPR in order to sur-
been postulated that the IRE1-XBP1 axis as well as the vive ER stress resulting from production of
PERK pathway are responsible for the maintenance of immunoglobulins and lysosomal compartments in
cellular homeostasis during larval development [270]. order to reach maturity [279–281]. One physiological
Pronephros formation was shown to be BiP dependent function that is indispensable for survival is the innate
in Xenopus embryos, where BiP morpholino knock- immune response, and cell differentiation is at its epi-
down not only blocked pronephros formation but also centre. The conversion of B lymphocytes to highly
attenuated retinoic acid signalling, impacting markers secretory plasma cells is accompanied by a huge expan-
such as the Lim homeobox protein [271]. In early sion of the ER compartment, and genetic alterations to
mouse development, it was shown that the BiP pro- induce immunoglobulin production are good examples
moter is activated in both the trophoectoderm and of the necessity of ER signalling in normal physiology
inner cell mass at embryonic day 3.5 and that absence [123]. This is supported by a study that suggests the
of BiP leads to proliferative defects and inner cell mass UPR, and the PERK pathway in particular, govern the
apoptosis, suggesting it is necessary for embryonic cell integrity of the haematopoietic stem-cell pool during
growth and pluripotent cell survival [272]. Furthermore, stress to prevent loss of function [282]. The ability of
mouse studies revealed that ER stress proteins such as skin fibroblasts to produce collagens and matrix metal-
BiP, GRP94, calreticulin and PDIA3 were downregu- loproteinases (proteins increased at wound sites), along
lated in adult neural tissues compared to embryonic with their ability to differentiate into myofibroblasts,
ones, suggesting a pivotal role for ER stress signalling provides another example where physiological ER
in the development of neural tissues such as the brain stress may drive morphological cellular transition [283].
and retina [273]. Beyond the nervous system, ER stress Although not yet fully characterized, the RIDD path-
signalling impairment has repeatedly shown mouse way has been linked to a multitude of physiological
embryonic lethality and, in particular in the hepatocel- processes including lysosomal degradation and xenobi-
lular system, multiple studies have demonstrated that otic metabolism through cytochrome P450 regulation
IRE1 and XBP1 signalling defects lead to fetal liver [284]. At the same time, substrates of regulated
hypoplasia, intrauterine anaemia and early antenatal intramembrane proteolysis such as CREBH are
pancreatic dysfunction [274]. The UPR is intrinsically involved in normal physiological processes such as glu-
linked to the mouse embryonic morula–blastocyst tran- coneogenesis [284]. Another substrate of regulated
sition [275] and this, in combination with evidence that intramembrane proteolysis, OASIS, is involved in mul-
there is an immediate postnatal downregulation of BiP, tiple stages of bone homeostasis and development.
shows that there is an important role for the UPR both Mice lacking OASIS present with severe osteopenia,
in early and late gestation [276]. Taking all this evidence which is compounded by the fact that the gene for type
into consideration, it is apparent that the correct inte- 1 collagen is an OASIS target [285]. Moreover, osteo-
gration of signals both intracellularly and between the blast OASIS expression is controlled by factors essen-
developing oocyte, follicular environment and support- tial to osteogenesis (BMP2), pointing to a PERK-
ing cumulus cells is absolutely essential for embryonic eIF2a-ATF4 pathway upregulation during osteoblast
differentiation, where ATF4 restores deficiencies of IRE1 RIDD activity is responsible for a reduction in
PERK null osteoblasts all the while impacting apopto- the mRNA of proinsulin processing proteins, including
sis for bone remodelling [251,286]. Furthermore, a link INS1, PC1 and SYP. These effects can be observed in
between osteoblast differentiation and hypoxia has cases of XBP1 deficiency and in cases of extensive
been established, with decreased vascularization shown UPR activation, highlighting the divergent effects of
in OASIS null mice pointing towards a potential role IRE1 RNase activity [119,221,294].
of ER stress in angiogenesis during bone development
[287]. This signalling cascade does not only restrict
Amino acid metabolism
itself to the normal physiology of bone but also modu-
lates UPR signalling in astrocytes and is responsible The UPR is also described to be involved in amino
for the terminal, early to mature, goblet cell differentia- acid metabolism. It was recently described that ATF4
tion in the large intestine [288–290]. mediates increased amino acid uptake upon glutamine
deprivation [295]. Furthermore, a low protein diet
leads to the upregulation of cytokines mediated by
Metabolism
IRE1 and RIG1 which results in an anticancer
The ER is a site of significant metabolic regulation. immune response in tumours [296]. In summary, these
The UPR plays a major role in the regulation of gly- findings show the importance of the various UPR
colysis and it was recently shown that IRE1 mediates arms in cell metabolism and energy homeostasis with
a metabolic decrease upon glucose shortage in neu- effects not only on the cell itself but also on the whole
rons, suggesting an important role for the UPR as an cellular environment.
adaptive response mechanism in relation to energy
metabolism [291]. Moreover, mTOR signalling adjusts
Pharmacological targeting of the UPR
global protein synthesis, which is a highly energy con-
suming process, and thereby regulates energy metabo- Several small molecules have been reported to modu-
lism (reviewed in [292]). late (activate or inhibit) one or more arms of the
UPR. Importantly, these molecules have shown
promising beneficial effects in diverse human diseases
Lipid homeostasis
(Table 1). X-ray cocrystal structures are now available
The ER is heavily involved in lipid homeostasis. Char- for IRE1 and PERK with several endogenous or
acteristically, hepatocytes are enriched in SER, because exogenous ligands. The understanding of how small
in addition to protein synthesis, these cells also synthe- molecules bind to the active sites and modulate the
size bile acids, cholesterol and phospholipids. XBP1 function of IRE1 and PERK will have a profound
ablation in murine liver results in hypolipidaemia due impact on the structure-based drug discovery of novel
to feedback activation of IRE1 caused by the lack of UPR modulators. Available X-ray structures, in addi-
XBP1. Activated IRE1 induces the degradation of tion to mutagenesis analysis of critical amino acids
mRNAs of a cohort of lipid metabolism genes via [297], have revealed a variety of unexpected allosteric
RIDD, demonstrating the critical role of IRE1–XBP1 binding sites on IRE1 [297–299].
signalling in lipid metabolism and suggesting that tar-
geting XBP1 may be a viable approach to the treat-
Pharmacological modulators of IRE1
ment of dyslipidaemias [113]. It was also reported that
in hepatocyte-specific IRE1-null mice, XBP1 is IRE1 signalling information along with CHOP/Gal4-
involved in very low-density lipoprotein synthesis and Luc cells and UPRE-Luc engineered cells were used to
secretion [215]. Interestingly, ATF6 has also been screen large chemical libraries in high throughput
shown to have a role in adipogenesis by inducing adi- screening assays for discovery of pathway-selective
pogenic genes and lipid accumulation [293]. modulators of IRE1 [300].
Glucose metabolism IRE1 ATP-binding site

The UPR is also involved in regulating glucose meta- IRE1 modulators have been discovered primarily by
bolism. Initial murine studies suggested the PERK– traditional drug discovery methods, identifying inhibi-
eIF2a arm was responsible for impaired insulin sig- tors specific to the kinase or RNase domain (Table 1).
nalling due to knock out effects on beta cells during The IRE1 kinase modulators were used as tools to
development. Further studies have since shown that understand the allosteric relationship between the
Table 1. Different modulators that target the UPR-transducer protein pathways. Molecule name, respective molecular target and brief
description with the associated reference are provided (ND: not determined).
UPR Arm Name Target Brief description Reference
PERK GSK2656157 PERK Kinase In preclinical stage for multiple myeloma [314,364]
and pancreatic cancer
Salubrinal GADD34/PP1c Inhibition of eIF2a dephosphorylation [365–367]
In ALS, it increases lifespan of mutant
superoxide dismutase 1 transgenic mice
In Parkinson’s disease, it increases neuronal
survival of a-synuclein transgenic mice
ISRIB eIF2b Decreased ATF4 expression [322]
Guanabenz GADD34/PP1c Inhibitor of eIF2a phosphatase, [368]
Sephin1 GADD34 (PP1c) Inhibitor of eIF2a phosphatase [369]
IRE1 Salicylaldimines IRE1 RNase IRE1aRNase active-site inhibitor [305]
STF-083010 IRE1 RNase IRE1a RNase active-site inhibitor [308]
In preclinical stage for multiple myeloma treatment
MKC-3946 IRE1 RNase IRE1a RNase active-site inhibitor [307,370]
4l8c IRE1 RNase IRE1a RNase active-site inhibitor [306]
APY29 IRE1 Kinase IRE1a kinase active-site inhibitor [303]
Sunitinib IRE1 Kinase IRE1a kinase active-site inhibitor [85,304]
FDA approved for renal cell carcinoma
It acts on multiple kinases
KIRA IRE1 Kinase IRE1a kinase active-site inhibitor [371]
Toyocamycin IRE1 RNase IRE1a RNase active-site inhibitor [309,372]
In preclinical stage for various cancers treatment
3-ethoxy-5,6- IRE1 RNase IRE1a RNase active site inhibitor [305]
dibromosalicylal-
dehyde
Apigenin Proteasome Increase of IRE1a nuclease activity in model [373]
FIRE peptide IRE1 Kinase Modulation IRE1 oligomerization in vitro, [85]
Xbp1 mRNA cleavage in vitro, in cell culture
and in vivo (Caenorhabditis elegans)
ATF6 Apigenin ATF6 Upregulation of ATF6 expression [373]
Baicalein ATF6 Upregulation of ATF6 expression [374]
Ceapin ND Inhibitor of ATF6 [323]
Kaempferol ATF6 Downregulation of ATF6 expression [375]
Melatonin ATF6 Inhibitor of ATF6 [325]
Compound 147 ATF6 Activator of ATF6 [376]
Compound 263 ATF6 Activator of ATF6 [376]
16F16 PDI Inhibitor of PDI [377]
kinase and RNase domains [301,302]. Kinase inhibi- inhibit the phosphorylation but stabilize the active
tors can be broadly classed as (a) ATP-competitive form of the kinase domain. An active kinase confor-
inhibitors that inhibit the kinase domain and activate mation is seen in human apo dP-IRE1* (PDB 5HGI),
the RNase domain and (b) ATP-competitive inhibitors as a back-to-back dimer. Notably, the DFG motif
that inhibit the kinase domain and inactivate RNase (Asp711-Phe712-Gly713) faces into the active site
(kinase inhibiting RNase attenuators – KIRAs). Avail- (DFG-in), with helix-aC-in conformation. In contrast,
able IRE1 crystal structures reveal a possible mecha- human IRE1 bound to KIRA compound 33 (PDB:
nism of RNase activation by conformational changes 4U6R) shows an inactive kinase conformation, with
that occur in the kinase domain when transitioning DFG-in and helix-aC-out conformation. The inactive
from a monomeric to an active dimeric state. Type I conformation is incompatible with back-to-back dimer
IRE1 kinase inhibitors include APY29 [303] and suni- formation due to the displaced helix-aC [301]. Imida-
tinib [304], which target the ATP-binding site and zopyrazine-based inhibitors and other KIRAs
allosterically inhibit the RNase activity of phosphory- was also the first oral small molecule to prevent neu-
lated IRE1 by possibly displacing helix-aC from an rodegeneration in vivo in prion-diseased mice, with
active conformation to an inactive conformation [301]. GSK2606414 reducing the levels of p-PERK and p-
eIF2a and restoring protein synthesis rates [316].
Despite the promising selectivity profile, pharmacologi-
IRE1 RNase-binding site
cal inhibition of PERK in mice caused damage to exo-
IRE1 RNase inhibitors include salicylaldehydes [305] crine cells and pancreatic beta cells, a similar
4l8C [306], MKC-946 [307], STF-83010 [308], toy- phenotype to that observed in PERK/ mice [317].
ocamycin [309] and hydroxyl-aryl-aldehydes [86]. The Furthermore, GSK2606414 and GSK2656157 were
reported cocrystal structures of murine IRE1a with found recently to inhibit RIPK1 at nanomolar concen-
salicyaldehyde-based inhibitor show that Lys 907 is trations [318]. To overcome the b-cell toxicity, small
involved in Schiff base arrangement (PDB code: 4PL3 molecules modulating the eIF2a pathway without
[86]). Lys 907 is a crucial residue present within the directly inhibiting PERK were examined. Integrated
hydrophobic pocket of the IRE1 RNase catalytic site stress response inhibitor (ISRIB) is the first small
[310]. Quercetin is reported to activate IRE1 through a molecule described to bind and activate guanine
site distinct from the nucleotide-binding site (crystal nucleotide exchange factor eIF2B [319,320]. Unlike
structure PDB 3LJ0), increasing the population of GSK inhibitors, ISRIB did not show any pancreatic
IRE1 dimers in vitro [299]. A recent in silico study toxicity [321]. Interestingly, ISRIB increased learning
identified the anthracycline antibiotic doxorubicin as and memory in WT mice [322] (Table 1).
an inhibitor of the IRE1-XBP1 axis [311]. Covalent
binders are very efficient in the sense that they com-
ATF6 modulators
pletely block the proteins to which they bind, but this
can also have several drawbacks [312]. Noncovalent The identification of small molecules that modulate
kinase and allosteric modulators in general inhibit ATF6 has been challenging due to lack of potentially
competitively and are thus less efficient, but can at the druggable binding sites and unavailability of the pro-
same time be extremely useful in obtaining new tein crystal structure. Recently, Walter and colleagues
insights for developing selective and potent modulators identified selective inhibitors of ATF6 signalling, the
of IRE1a-XBP1 signalling (Table 1). small molecules Ceapins, using a high throughput
cell-based screen [323]. Ceapins do not affect the
IRE1 and PERK arms of the UPR. Ceapins are
Other IRE1 modulators
chemically classed as pyrazole amides and extensive
Peptides derived from the kinase domain of human biochemical and cell biology evidence show that they
IRE1 promote oligomerization in vitro, enhancing trap ATF6 in the ER and thus prevent its transloca-
XBP1 mRNA cleavage activity in vitro and in vivo tion to the Golgi upon stress [324]. Ceapins sensitize
[85]. However, although peptide-based modulators cells to ER stress without affecting unstressed cells
have limited clinical application [313] (Table 1) peptide and hence have potential to be developed within the
mimetics may prove more useful. These are different framework of a therapeutic strategy to induce cell
aspects that can be exploited to develop selective IRE1 death in cancer cells. A recent study identified mela-
modulators. Despite significant progress in understand- tonin as an ATF6 inhibitor, leading to enhanced liver
ing IRE1 signalling and in the development of modu- cancer cell apoptosis through decreased COX-2
lators of IRE1 activity, several questions still remain expression [325]. The activation of ATF6 depends on
to be answered to fully control IRE1 activity and sig- a redox process involving PDIs suggesting that PDI
nalling outcomes, including how to selectively target inhibitors such as PACMA31 [326], RB-11-ca [327],
the XBP1 and RIDD arms of IRE1 signalling. P1 [327] and 16F16 [328] may be able to modulate
ATF6 activation. Additionally, the serine protease
inhibitor 4-(2-aminoethyl) benzenesulfonyl fluoride is
Pharmacological modulators of PERK
reported to prevent ER stress-induced cleavage of
Through biochemical screening of exclusive library col- ATF6 [329] (Table 1). Albeit the above developments
lections and structure-based lead optimization, GSK hold strong promise for the future, very little is
discovered PERK inhibitors GSK2606414 and known to date about specific binding sites, which
GSK2656157 [314]. These potent PERK inhibitors can together with the lack of a crystal structure and
be orally administered [314], reducing tumour growth insufficient templates to enable homology modelling,
in mouse xenograft models [314,315]. GSK2606414 rational drug design targeting ATF6 remains a
challenge. Availability of an ATF6 crystal structure is patients to test the association of 20 SNPs across the
in this sense the key aspect, as this will provide ato- XBP1 gene region, it was found that three SNPs
mistic level understanding of interactions and mecha- rs5997391, rs5762795 and rs35873774 are associated
nism of action, and enable in silico based rational with disease, thus linking cell-specific ER stress
design of ATF6 modulators. changes with the induction of organ-specific inflamma-
tion. Quantitative changes in ER stress chaperones in
the CSF have been proposed as possible biomarkers to
The UPR in the clinic
monitor the progression of neurodegenerative diseases
In this section, we review recent preclinical and clinical such as ALS [338,339]. Finally, the mesencephalic
studies in which UPR components were used as dis- astrocyte-derived neurotrophic factor (MANF) can be
ease biomarkers or as therapeutic targets (Fig. 3). As used as a urine biomarker for ER stress-related kidney
already described in section Perturbing ER functions diseases [340]. MANF localizes in the ER lumen and
molecules have been designed to modulate ER stress is secreted in response to ER stress in several cell
by inducing the UPR (Brefeldin A, DTT), inhibiting types. Similarly, angiogenin was identified as an ER
SERCA Ca2+ ATPases (thapsigargin) or preventing stress responsive biomarker found in the urine of
the generation of glycoproteins, and hence, the induc- patients with kidney damage [341]. Thus, noninvasive
tion of ER stress through calcium imbalance or mis- ER stress-related biomarkers can be used to stratify
folded protein accumulation. They were touted as disease risk and disease development (Fig. 3).
potential antitumour therapies as they could poten-
tially induce tumour cell death through ER stress over-
ER stress and UPR-based therapies
activation. However, none of these compounds were
used in the clinic due to their lack of specificity and Beyond their use as biomarkers, ER stress signalling
high toxicity. It has been reported though that a pro- components also represent relevant therapeutic targets.
drug analogue of thapsigargin, mipsagargin, did dis- BiP was recently recognized as a universal therapeutic
play acceptable tolerability and favourable target for human diseases such as cancer and bacte-
pharmacokinetic profiles in patients with solid tumours rial/viral infections [333]. Antibodies targeting BiP
[330]. On the other hand, section 6 describes molecules exhibited antitumoural activity and enhanced radiation
that inhibit the various arms of the UPR. efficacy in non-small-cell lung cancer and glioblastoma
multiforme in mouse xenograft models [342]. It was
also shown that short-term systemic treatment with a
UPR biomarkers
monoclonal antibody against BiP suppressed AKT
Changes in UPR and ER stress markers in blood or activation and increased apoptosis in mice with
tissue biopsy samples can be indicative of disease state endometrial adenocarcinoma [343]. Moreover, the ER-
and could be/are utilized as valuable biomarkers for resident GRP94 is being evaluated as a therapeutic
different human pathologies. For instance, BiP has target because of its ability to associate with cellular
strong immunological reactivity when released into the peptides irrespective of size or sequence [344]. Preclini-
extracellular environment [331], and in 1993, it was the cal studies have linked GRP94 expression to cancer
first ER stress protein associated with the pathogenesis progression in multiple myeloma, hepatocellular carci-
of osteogenesis imperfecta [332]. Since then, further noma, breast cancer and colon cancer. Finally, this
evidence suggests overexpression of BiP in several protein has been identified as a strong modulator of
human diseases (reviewed in [333]). The UPR tran- the immune system that could be used in anticancer
scription factors can also be seen as potential biomark- immunotherapy [345].
ers of various diseases. ATF4 is upregulated and ER stress-induced transcription factors can also rep-
contributes to progression and metastasis in patients resent relevant targets. Thus, XBP1s has been one of
with oesophageal squamous cell carcinoma [334]. Simi- the main targets for drug discovery and gene therapy
larly, XBP1 overexpression is linked to progressive [346]. Elimination of XBP1 improves hepatosteatosis,
clinical stages and degree of tumour malignancy in liver damage and hypercholesterolaemia in animal
osteosarcoma [335]. In contrast, IRE1–XBP1 downreg- models. As such direct targeting of IRE1 or XBP1 can
ulation can differentiate germinal centre B cell-like be a possible strategy to treat dyslipidaemias [113]. In
lymphoma from other diffuse large B-cell lymphoma cancer, toyocamycin was shown to inhibit the constitu-
subtypes and contributes to tumour growth [336]. tive activation of XBP1s expression in multiple mye-
Moreover, XBP1 is genetically linked to inflammatory loma cells as well as in patient primary samples [309].
bowel disease (IBD) [337]. Using cohorts of IBD Despite being the least studied UPR arm, there are
Fig. 3. UPR disease biomarkers and therapeutic targets. Schematic representation of the UPR signalling pathway as defined in Fig. 2 and
annotated with the relevance to disease of each component. The colour code indicates the type of disease (cancer: orange; metabolic
disease: red; degenerative disease: blue; infectious disease: green; inflammatory disease: pink) and the lines indicate the role as biomarker
(continuous line) or therapeutic target (dashed line).
instances that ATF6 can be a specific clinical target. that expression of orosomucoid-like 3 (ORMDL3) reg-
The activation of ATF6 but not IRE1 or PERK has ulates ATF6 expression and airway remodelling
been linked with airway remodelling in a mouse model through ATF6 target genes such as SERCA2b,
of asthma [347]. Additionally, these studies showed TGFb1, ADAM8 and MMP9 (Fig. 3, Table 2).
ER stress targets are also strong candidates for reported as well in different critical care diseases mod-
immunotherapy and vaccines development, a good els, such as sepsis [331,332], liver, heart, brain and kid-
example of which is the production of chaperone pro- ney ischaemia [353–359] and haemorrhagic shock
tein-based cancer vaccines termed chaperone-rich cell [334,335]. But, the pathophysiological impact of ER
lysate (CRCL) [348]. The CRCL are purified from stress activation in these conditions severely lacks
tumour tissue or recombinantly produced and applied characterization. Multiple factors such as inflamma-
as vaccines against murine and canine cancers or infec- tion, hypoxia present in sepsis and shock can induce
tious diseases. Advantages of CRCL vaccines include ER stress but its effects are ambivalent. It has been
small quantities and easily obtained starting materials shown that induction of ER stress is cytoprotective
[349]. Furthermore, DNA vaccination with gp96-pep- [353,354], and that proteostasis promotors/disruptors
tide fusion proteins showed increased resistance such as 4-PBA [336] or TUDCA [337] can be used to
against the intracellular bacterial pathogen Listeria improve disease outcome. The increase of CHOP in
monocytogenes in a mouse model [350]. To improve renal tissue was reported to inhibit inflammatory
the efficacy of gp96 vaccines, gp96 was pooled with response in and provide protection against kidney
CpG in combination with anti-B7H1 or anti–inter- injury [336]. Moreover, the activation of PERK seems
leukin-10 monoclonal antibodies to treat mice with to facilitate survival of lipopolysaccharide-treated car-
large tumours [351]. The heterogeneous or allogeneic diomyocytes by promoting autophagy [338]. Addition-
gp96 vaccines protected mice from tumour challenge ally, the activation of ATF6 before ischaemia reduced
and re-challenge. In addition to its role as a molecular myocardial tissue damage during ischaemia/reperfusion
chaperone, GRP94 was likewise identified as a peptide (I/R) injury [339]. Furthermore, induction of BiP in
carrier for T-cell immunization [352]. However, the cardiomyocytes stimulated AKT signalling and pro-
immunological application of GRP94 derived from its tected against oxidative stress, conferring cellular I/R
peptide binding capacity was not further investigated damage protection [340]. In contrast, inhibition of ER
(Fig. 3, Table 2). The activation of ER stress has been stress was indicated to limit cellular damage in
Table 2. ER stress-centred clinical trials. A range of clinical entities in endocrinology, oncology and paediatrics have been targeted through
clinical trials. This table presents such trials detailing the trial targeted, interventional agent investigated and national authority carrying out
the investigation.
Trial Disease Intervention Country
Role of ER stress in the pathophysiology • Diabetes mellitus, type 2 No intervention France

of type 2 diabetes
ER stress and resistance to treatments • Polycythemia vera Biological: RNA sample France
in Ph-negative myeloproliferative neoplasms • Essential thrombocythemia of total leucocytes
before start of treatment
Effect of ER stress on metabolic function • Insulin resistance Drug: TUDCA United States
• Diabetes Other: placebo
• Obesity
Drug: sodium phenylbutyrate
ER stress in chronic respiratory diseases • Chronic airway disorders Observational South Korea
• Lung cancer
TUDCA for protease-inhibitor associated • HIV-related insulin resistance Drug: TUDCA United States
insulin resistance • Protease inhibitor-related Insulin Other: placebo tablet
resistance
ER stress in NAFLD • Obesity Drug: methyl-D9-choline United States

• NAFLD
TUDCA in new-onset type 1 diabetes • Type 1 diabetes Drug: TUDCA United States
Drug: Sugar Pill (placebo)
Effects of Liraglutide on ER stress in • Type 2 diabetes Drug: liraglutide United States
obese patients with type 2 diabetes
A clinical trial of dantrolene sodium in • Wolfram syndrome Drug: dantrolene sodium United States
paediatric and adult patients with • Diabetes mellitus
wolfram syndrome
• optic nerve atrophy
• Ataxia
mechanisms for fine-tuning ER signalling, as well as

Box 1. First-in-human trial
motivated the need for their better characterization
Intravenous infusion of GRP78/BiP is safe in patients
towards relevant health-related applications. This drive
In 2006, Brownlie et al. [362] reported that the prophy-
to further ER knowledge has also led to the identifica-
lactic or therapeutic parenteral delivery of BiP amelio-
tion of emerging roles for the ER in physiology and
rates clinical and histological signs of inflammatory
disease. In particular, it appears an indispensable tool
arthritis in mice. Ten years later, the first human clinical
for cellular communication that reaches beyond the
trial using intravenous BiP demonstrated that GRP78/
intracellular space. The concept of transmissible ER
BiP is safe in patients with active rheumatoid arthritis
stress illustrates the far-reaching control that ER sig-
and some patients had clinical and biological improve-
nalling exerts in interorgan communication affecting
ments [363]. In phase I/IIA RAGULA trial, 42 patients
disease pathogenesis and normal physiology [360,361].
were screened, and 24 were randomized to receive either
Our increasing knowledge of ER signalling mecha-
BiP or placebo. The study showed that after a single
nisms presents opportunities to exploit the resulting
intravenous infusion, BiP may induce remission lasting
applications on multiple fronts, including bioengineer-
up to 3 months in rheumatoid arthritis patients.
ing and health, concepts that may routinely overlap.
For example, boosting ER protein production capacity
may be applied to cell engineering to increase biologic
therapy production. This will drive down costs of bio-
logics, helping demand to be met and leading to more
pathologies such as hepatic I/R [341]. This contradic- widely available medications, thus having a significant
tion may be due to interference between UPR and effect on public health. Population-wide consequences
inflammatory pathways. CHOP-/- mice were reported of ER modulation may not be restricted to the pro-
to have more prominent increase in NF-kB activation duction of biologic therapies as its applications could
and further upregulation of proinflammatory genes also contribute to bioengineering approaches for crop
(CXCL-1, MIP-2, IL-6) [342]. Interestingly, inhibition or livestock improvement.
of IRE1-NF-kB by resveratrol protected against sep- A thorough understanding of the ER stress response
sis-induced kidney failure [343]. In this light, the mod- and its role in physiology and pathophysiology can be
ulation of specific UPR branches is promising applied to develop new ER stress targeted therapies
approach for therapy of critical care diseases. and stratifying patients into cohorts suitable for ER-
As discussed above, understanding and characteriz- targeted therapies. Considering the enormity of attri-
ing the UPR has provided several potential targets to tion rates of novel therapeutic discovery in an ever-
develop new therapeutics for various diseases, with an tightening financial climate, there is an urgent need for
encouraging increase in the number of clinical trials new therapeutic targets as well as precision tools that
based on ER stress pathway targets or associated target and guide innovation to specific patient pools.
drugs. Several of these trials [ClinicalTrials.gov, Euro- ER stress signalling may provide such tools. Not only
pean Clinical Trials Database and the ISRCTN reg- is it central to life itself but it is involved in a wide
istry] have focused on diabetes mellitus. A trial testing array of clinical presentations. Moreover, its effect on
TUDCA and 4-PBA for the treatment of high lipid heterogeneous presentations within the same diseases
levels or insulin resistance was conducted by the makes it an attractive target for translational precision
Washington University School of Medicine; however, medicine. Of course, when undertaking medical
although this study was completed in 2014, the find- research or trying to solve a biomolecular functional
ings are not available yet. The results from the first mystery one cannot look past the logistical aspect of
completed human trial using BiP for rheumatoid the task ahead. The conserved metazoan nature of ER
arthritis are described in Box 1. We can anticipate that stress signalling combined with the emergence of high
clinical trials to test ER stress targeting drugs in sev- throughput and in silico strategies supplies researchers
eral other diseases will shortly ensue. with a wealth of tools to study pathophysiology, from
structure to function in multiple in vivo and in vitro
models, producing robust results to be put forward for
Concluding remarks
clinical scrutiny while all the while observing both the
The ER has evolved in our knowledge from a key safeguards of the declaration of Helsinki and ethics on
player in proteostasis and the secretory pathway to a animal experimentation. Our deeper understanding of
cornerstone of metabolic functions. Such wealth of the ER and its major homeostatic regulator, the UPR
information has allowed the identification of numerous response, is introducing an individualized molecular
approach to health management at a preventative, endolysosomal interorganelle tethering protein. J Cell

diagnostic and therapeutic level and, uncovering the Biol 210, 541–551.
genetic architecture underlying the ER stress response 13 Hayashi-Nishino M, Fujita N, Noda T, Yamaguchi A,
could significantly influence future therapeutic strate- Yoshimori T & Yamamoto A (2010) Electron
gies in patients. tomography reveals the endoplasmic reticulum as a
membrane source for autophagosome formation.
Autophagy 6, 301–303.
Acknowledgements 14 Uemura T, Yamamoto M, Kametaka A, Sou Y,
Yabashi A, Yamada A, Annoh H, Kametaka S,
We apologize to colleagues whose work was not cited
Komatsu M & Waguri S (2014) A cluster of thin
due to space limitation. This work was funded by
tubular structures mediates transformation of the
grants from EU H2020 MSCA ITN-675448 (TRAI-
endoplasmic reticulum to autophagic isolation
NERS) and MSCA RISE-734749 (INSPIRED). CMP
membrane. Mol Cell Biol 34, 1695–1706.
lab is funded by CERCA, FEDER (A Way To
15 Stefan CJ, Manford AG, Baird D, Yamada-Hanff J,
Achieve Europe) and MINECO (BFU2016-78154-R). Mao Y & Emr SD (2011) Osh proteins regulate
phosphoinositide metabolism at ER-plasma membrane
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Endoplasmic reticulum stress signalling – from basic

Keywords The endoplasmic reticulum (ER) is a membranous intracellular organelle

(Received 18 March 2018, revised 24 June

Introduction whereby ER tubules possess a high membrane curva-

Glucose metabolism for the cell to regulate metabolism through regulating

Glucose metabolism IRE1 ATP-binding site

UPR Arm Name Target Brief description Reference

Trial Disease Intervention Country

Role of ER stress in the pathophysiology • Diabetes mellitus, type 2 No intervention France

ER stress in NAFLD • Obesity Drug: methyl-D9-choline United States

mechanisms for fine-tuning ER signalling, as well as

approach to health management at a preventative, endolysosomal interorganelle tethering protein. J Cell

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