Autophagy and Disease: Always Two Sides To A Problem: Invited Review

INVITED REVIEW
Journal of Pathology
J Pathol 2012; 226: 255273
Published online in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/path.3025
Autophagy and disease: always two sides to a problem
Sunandini Sridhar,
1
Yair Botbol,
2
Fernando Macian
2,3
and Ana Maria Cuervo
1,3
*
1
Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, New York, USA
2
Department of Pathology, Albert Einstein College of Medicine, New York, USA
3
Institute for Aging Studies, Albert Einstein College of Medicine, New York, USA
*Correspondence to: Ana Maria Cuervo, Department of Developmental and Molecular Biology, Institute for Aging Research, Albert Einstein
College of Medicine, Chanin Building, Room 504, 1300 Morris Park Avenue, Bronx, NY 10461, USA. e-mail: [email protected]
Abstract
Autophagy is a process traditionally known to contribute to cellular cleaning through the removal of intracellular
components in lysosomes. In recent years, intensive scrutiny at the molecular level to which autophagy has been
subjected has also contributed to expanding our understanding of the physiological role of this pathway. Added
to the well-characterized role in quality control, autophagy has proved to be important in the maintenance of
cellular homeostasis and of the energetic balance, in cellular and tissue remodelling, and cellular defence against
extracellular insults and pathogens. It is not a surprise that, in light of this growing number of physiological
functions, connections between autophagic malfunction and human pathologies have also been strengthened. In
this review, we focus on several pathological conditions associated with primary or secondary defects in autophagy
and comment on a recurring theme for many of them, ie the fact that autophagy can often exert both benecial
and aggravating effects on the progression of disease. Elucidating the factors that determine the switch between
these dual functions of autophagy in disease has become a priority when considering the potential therapeutic
implications of the pharmacological modulation of autophagy in many of these pathological conditions.
Copyright 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Keywords: cancer; cardiomyopathy; immunity; lysosomes; neurodegeneration; protein aggregation; proteolysis; proteotoxicity; T cell
function
Received 6 August 2011; Revised 25 September 2011; Accepted 3 October 2011
No conicts of interest were declared.
Introduction to autophagy
The Greek term autophagy (self-eating) was coined
almost half a century ago by Christian DeDuve [1].
Today, this intensely investigated pathway has come
to be recognized as an evolutionarily conserved intra-
cellular process through which cytosolic components,
ranging from proteins, lipids, sugars and nucleotides to
whole organelles and invading pathogens, are targeted
for lysosomal degradation [2,3]. Autophagy contributes
to both the removal of damaged long-lived proteins and
organelles and the normal turnover of these intracellu-
lar components as part of its role in cellular quality
control. In addition, autophagy also serves as a cellu-
lar adaptive response to compromised conditions, such
as metabolic stress, when degradation of intracellular
materials through this pathway becomes an alternative
source of energy [4].
In recent years, a growing number of functions have
been added to these two basic cellular functions of the
autophagic processquality control and maintenance
of the cellular energetic balancehelping to shape the
physiological relevance of this pathway. Furthermore, a
better understanding of the molecular mechanisms that
mediate the autophagic process has helped to establish
connections between autophagy and the pathogenesis
of different disorders and of ageing [3,5,6]. Findings
in recent years also support the existence of more
than one type of autophagy and the fact that different
autophagic pathways co-exist in most cells. In this
review, we briey describe the main characteristics
and molecular components of the different autophagic
variants and then provide a general view of the multiple
physiological functions of this cellular process. In the
second part, we comment on specic autophagy-related
pathologies, which either result from a primary defect
in the autophagic process, or for which changes in
autophagy have been described to exert a modulatory
effect on the course of the disease.
The molecular dissection of the different
autophagic pathways
To date, three basic forms of autophagy have been
described, namely, macroautophagy, microautophagy
and chaperone-mediated autophagy (CMA), which pri-
marily differ in the way in which cytosolic components
(cargo) are delivered to lysosomes [2,7,8] (Figure 1).
Macroautophagy and microautophagy were both rst
Copyright 2011 Pathological Society of Great Britain and Ireland. J Pathol 2012; 226: 255273
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256 S Sridhar et al
Figure 1. Autophagic pathways. Three different general mechanisms of lysosomal delivery of cargo set the basis for the different types
of autophagy described in mammalian cells. (A) Macroautophagy: different extra- and intracellular signals activate the recruitment of
the macroautophagy initiation complex to the sites of autophagosome formation. Shuttling of proteins and lipids to these regions and
posttranslational modications of the lipids initiate the formation of a limiting membrane, which grows through the assembly of proteins
conjugated to proteins or lipids while it sequesters components of the cytosol. Once the membrane seals to form the autophagosome,
this double membrane vesicle is delivered to lysosomes where, upon membrane fusion, lysosomal hydrolases gain access to cargo.
(B) Microautophagy: through stimuli that remain poorly identied, cytosolic soluble proteins and organelles are directly sequestered by
invaginations in the boundary membrane of lysosomes and late endosomes. Cargo internalized in the small luminal vesicles is degraded
after the vesicles pinch off from the limiting membrane. Although most microautophagy probably occurs in bulk, selective targeting by
hsc70 of cytosolic proteins to microvesicles as they form in late endosomes has also been described. (C) Chaperone-mediated autophagy
(CMA) is induced by stimuli such as prolonged starvation, oxidative stress and other conditions resulting in protein damage, but the
signalling mechanism activated by these stimuli remains unknown. When CMA is activated, selective cytosolic proteins bearing a targeting
motif are recruited by hsc70 and co-chaperones to the surface of lysosomes. Upon binding to the receptor protein LAMP-2A, substrates
cross the membrane through the LAMP-2A-dependent translocation complex and are then rapidly degraded in the lumen.
described as mechanisms for in-bulk sequestra-
tion of cytoplasmic components (including entire
organelles) into vesicular compartments. In macroau-
tophagy, these vesicles form de novo from a limit-
ing membrane of non-lysosomal origin that seals upon
itself to form free-standing double membrane carriers
known as autophagosomes [9,10]. Fusion of lysosomes
with the limiting membrane of the autophagosome
grants lysosomal hydrolases access to the sequestered
cargo, assuring its complete degradation. In the case
of microautophagy, the engulfment of cargo occurs
through deformation of the lysosomal membrane itself,
to form vesicles that invaginate towards the lysoso-
mal lumen [11,12]. Pinch-off of these vesicles from
the lysosomal membrane into the lumen, and the sub-
sequent degradation of their limiting membrane by the
lysosomal hydrolases, precede cargo degradation.
Both macroautophagy and microautophagy were ini-
tially described in mammalian cells, but their molec-
ular characterization has been mostly carried out in
yeast, taking advantage of the genetic analysis that can
be performed in this model organism. These genetic
screenings have identied that more than 30 differ-
ent genes (known as ATG or autophagy-related genes)
participate in the execution and regulation of macroau-
tophagy [2,13] (Figure 1). The protein products of
these genes (Atg or autophagy-related proteins) orga-
nize into functional complexes that mediate the fol-
lowing steps in the autophagic process: nucleation
of the limiting membrane, elongation of the mem-
brane, sealing to form a vesicle and fusion of the
double membrane vesicle with lysosomes. Nucleation
is attained through post-translational modications of
pre-existing lipids in the membranes of different intra-
cellular organelles [endoplasmic reticulum (ER), mito-
chondria, Golgi] as well as in the plasma membrane
[1416]. Coordinated recruitment of lipid-modifying
enzymes and proteins at the place of autophagosome
formation gives rise to the limiting membrane [17].
Growth of this membrane occurs through two enzyme-
regulated processes that mediate conjugation of (1) a
proteinlight chain protein 3 or LC3to one of the
constituent membrane lipids and (2) of two cytoso-
lic proteins (Atg5 and Atg12) between them [9,18].
SNARE-like proteins, molecular motors and additional
lipid-modifying enzymes (phosphatases and kinases)
participate in autophagosome-lysosome fusion. Most
of the regulatory components exert their action on
the nucleation complexes. For example, the Target of
The pathophysiology of autophagy 257
Rapamycin, a well-characterized negative regulator of
this pathway, prevents the recruitment and interaction
of specic Atgs of the nucleation complex to the site
of autophagosome formation [1921]. Although less
is known about the regulation of later steps of the
autophagic process, recent studies have identied the
transcription factor EB as a global regulator of Atgs
that can up-regulate initiation, elongation and fusion,
as well as lysosomal biogenesis in response to nutri-
tional stress [22]. Homologues for most yeast Atgs
have been identied in many other species (Drosophila
[23], Caenorhabditis elegans [24], Dictyostelium [25],
Arabidopsis [26], Trypanosoma [27]) and in mammals,
where these genes often have several variants with
diverse functions [28].
The number of yeast genes shown to participate
in microautophagy does not exceed a dozen, but
this process also partially depends on Atgs shared
with macroautophagy [29]. Microautophagy-specic
proteins contribute to the formation and sealing of
the vacuolar membrane (equivalent of the lysosome in
yeast) [30]. Failure to identify mammalian homologues
of the yeast microautophagy genes initially led to the
proposal that microautophagy was not evolutionarily
conserved. However, recent studies show otherwise,
as a microautophagy-like process has been described
to occur in mammalian late endosomes. This process,
known as endosomal microautophagy, has adopted the
machinery involved in biogenesis of multivesicular
bodies to form the invaginating vesicles that sequester
cytosolic material for degradation [31].
In recent years, in addition to this in bulk non-
selective degradation of cytosolic components, specic
sequestration of cargo has also been described for
both macro- and microautophagy. In the case of selec-
tive macroautophagy, the distinctive characteristic is
the presence of a single type of cytosolic material in
autophagosomes, in clear contrast to the in-bulk pro-
cess, where heterogeneous cargo occupies the lumen
of the autophagosome. Selective forms of macroau-
tophagy are named depending on the sequestered mate-
rial, giving rise to terms such as mitophagy [32,33],
pexophagy [34,35], reticulophagy [36,37], lipophagy
[38], ribophagy [39] and aggrephagy [40]. Similar cri-
teria apply to selective forms of microautophagy, such
as micropexophagy [34,35] micronucleophagy [41,42]
and microglycophagy [43]. All these selective forms
of autophagy utilize the same essential components
of the autophagic machinery described for their in-
bulk variants, but they add an extra step related to
cargo recognition. A specic subset of proteins, known
as cargo-recognition proteins, have been involved in
this step and include, among others, p62, neighbour
of BRCA1 (NBR1), Nix and the PINK1/Parkin pair
[44,45]. These adaptor proteins connect the degra-
dation machinery with particular componentsoften
ubiquitin moietieson the surface of the cytosolic
organelle to be sequestered [44,46,47]. Cytosolic chap-
erones, in particular the heat shock cognate protein
of 70 kDa, or hsc70, and BAG-3, have also been
recently described to contribute to selective recogni-
tion of aggregates by macroautophagy in chaperone-
assisted selective autophagy (CASA) [48].
Selectivity is the distinctive feature of CMA, the
third type of mammalian autophagy, wherein particular
soluble proteins bearing in their sequence a pentapep-
tide targeting motif biochemically related to KFERQ,
are recognized by hsc70, which mediates their deliv-
ery to the lysosomes for direct translocation across
the lysosomal membrane [8,49] (Figure 1). Although
yeast genetic approaches could not be applied to the
molecular dissection of CMA, since this pathway has
so far been described only in mammals, about eight
different proteins have been identied to participate
in this pathway using biochemical procedures. Most
of the identied CMA components have promiscuous
functions and are shared with other intracellular pro-
cesses. Such is the case for the cytosolic chaperones
hsc70 and hsp90 [50,51] and the novel pair of reg-
ulators, glial brillary acidic protein and elongation
factor 1 [52]. Interestingly, lysosome-specic vari-
ants have been identied for each of these proteins,
suggesting that post-translational modications of the
cytosolic proteins determine their association with this
degradative compartment and their commitment to
CMA. So far, the only CMA-exclusive component is
the lysosome-associated membrane protein type 2A
(LAMP-2A), which acts as a receptor for substrates of
this pathway [53]. Once the cytosolic proteins destined
for CMA degradation bind to this single transmem-
brane protein, they promote its assembly into a higher-
order molecular complex required for translocation of
the CMA substrates into the lysosomal lumen [51].
Interested readers are referred to more focused
reviews [2,3,8,29,54] for a comprehensive description
of the molecular apparatus executing these different
autophagic pathways. For the purposes of this review,
the term autophagy will represent macroautophagy,
unless otherwise mentioned.
Physiological relevance of autophagy
As described in the Introduction, a growing number of
cellular functions have been attributed to autophagy.
We highlight here some of the best-characterized func-
tions that have contributed to expanding the physio-
logical relevance of this catabolic process. The role
of autophagy in cellular defence, by participating in
innate and adaptive immunity, is discussed in detail
in the section dedicated to autophagy and the immune
function.
Autophagy in the cellular energetic balance
Both macroautophagy and CMA are induced as an
acute adaptive response to a variety of metabolic
stressors, including, among others, nutrient starvation,
growth factor withdrawal, high lipid content chal-
lenges or hypoxia [4,5557]. Under these conditions,
258 S Sridhar et al
free amino acids (especially branched-chain amino
acids), released by autophagic proteolysis of intracel-
lular proteins and organelles, are recycled to main-
tain protein synthesis even when nutrients are scarce.
Autophagy in the liver converts this organ into a
main source of amino acids that are then delivered
to other organs through the blood stream during star-
vation [5,56,58,59]. In fact, the low plasma concen-
trations of essential amino acids and decreased ATP
levels in most tissues observed in autophagy defective
Atg5
/
and Atg7
/
neonates conrm the impor-
tance of this pathway during nutritional deprivation,
in this case as a result of the cessation in transpla-
cental nutrient supply at birth [60,61]. Amino acids
resulting from autophagic breakdown could also be
utilized for the production of cellular ATP through
direct oxidation, or by fuelling the TCA cycle and glu-
coneogenesis with intermediates such as oxaloacetate.
This contribution of amino acids to energy homeostasis
has been conrmed in specic conditions, such as in
the case of interleukin-3-deprived haematopoietic cells,
where the addition of TCA cycle substrates, such as
methylpyruvate, is enough to preserve cellular viability
[62]. However, amino acids are not an efcient source
of energy. Instead, the array of energy stores mobi-
lized by autophagy is now recognized to include more
energetically efcient molecules, such as lipids, glyco-
gen and nucleic acids. The hydrolytic products of these
molecules, free fatty acids, glucose and nucleotides,
can be funnelled into the TCA cycle, gluconeogenesis
or glycolysis to produce ATP [4,43].
This capability of autophagy to maintain ATP pro-
duction and support macromolecular synthesis makes
it a pro-survival pathway of particular importance in
organs with high energetic requirements, such as the
heart or skeletal muscles. Alterations of this specic
autophagic function also constitute the basis of some
common metabolic disorders.
Autophagy and cellular quality control
The proteome and cellular organelles are susceptible to
different toxic insults that can lead to the generation of
misfolded or modied soluble proteins, protein cross-
linking and oligomerization into high-order irreversible
structures or aggregates, and accumulation of defec-
tive, no longer functional, organelles that could become
harmful for the cells [6365]. Basal autophagy, often
referred to as quality control autophagy, is integral
to the cellular surveillance machinery responsible for
recognition and removal of these aberrant structures
[66,67]. Basal autophagy is particularly important in
non-dividing post-mitotic cells that cannot dilute the
cellular damage through division. For example, condi-
tional knock-out of the essential autophagy genes atg7
or atg5 in hepatocytes, neurons and cardiomyocytes
leads to marked accumulation of ubiquitin-positive pro-
tein aggregates and damaged organelles, even in the
absence of an added toxic challenge [60,68,69].
Exposure to stressors, such as oxidative stress, ER
stress or other conditions resulting in massive amounts
of unfolded proteins and organelle damage, elicits acti-
vation of inducible forms of autophagy [7073]. In this
context, activation of CMA contributes to the selec-
tive removal of soluble (aggregate-prone) proteins,
whereas macroautophagy facilitates the clearance of
protein aggregates [40,63,74,75] and whole organelles
[33,36,37]. However, it is possible that macroau-
tophagy ameliorates proteotoxicity not only through
aggregate removal but also by the in-bulk sequestra-
tion of still-soluble forms of the pathogenic proteins
before they aggregate [68,76,77]. Autophagy is also
important to restore organelle homeostasis [36,72,78],
to eliminate damaged organelles after stress [37,79]
and to assist cells to adapt their organelle content to
the changing environmental conditions (eg it controls
peroxisome number during nutrient auxotrophy or total
mitochondria mass for energetic balance) [80].
Autophagy-mediated control of protein and organelle
quality, as well as organelle number, is essential for the
maintenance of cellular homeostasis and to guarantee
cellular survival during stress.
Cellular remodelling and autophagy
Cellular differentiation often requires the elimination
of large subsets of proteins, nucleic acids or organelles
in order to switch into the next developmental stage or
nal differentiated state. Furthermore, cellular remod-
elling is an energy-demanding process often associ-
ated with nutrient-deprived developmental phases. It
is no surprise, therefore, that autophagy has emerged
through evolution as one of the favoured cellular
tools to accomplish these developmental remodelling
tasks. The capability to eliminate whole regions of the
cytosol, unique to some of the autophagy variants, and
its recycling properties underlie the important role that
this process plays during development. Autophagy has
been shown to be necessary in yeast during sporula-
tion [81], in C. elegans during dauer formation [24],
in Drosophila during the transition from the larval to
the pupal stage [82] and in Dictyostelium for switch-
ing from amoeba to fruiting body [25]. Examples
of autophagy-mediated differentiation events in mam-
malian cells include, among others, the removal of
maternal macromolecules during early embryogenesis
[83] and the clearance of mitochondria during ery-
throcyte [8486], lymphocyte [87,88] and adipocyte
[89,90] differentiation.
Autophagy in cellular death and cell survival
As indicated in the previous sections, the ability of
autophagy to assist cells to adapt to the changing envi-
ronment, to protect them against the damage caused by
toxic insults and to defend them from pathogens has led
to the classication of this pathway as a cell-survival
mechanism. However, interplay between autophagy
and mechanisms related to cell death have also been
described. The best-accepted example of autophagy as
a cell death effector is the degradation of the salivary
glands during pupal transition in Drosophila [82,91]. In
contrast, direct evidence of a similar role for autophagy
in mammals is sparse [92]. In fact, many of the orig-
inal claims of cell death by autophagy have cur-
rently been revised and reformulated as cell death
with autophagy, since the main support for autophagic
involvement in many of these cases was the obser-
vation of autophagic vacuoles in the dying cell [93].
Although an increase in the number of autophagic vac-
uoles could result from their increased formation, the
large capability of the lysosomal system often prevents
their accumulation by facilitating their rapid clearance.
It is more frequent that the increase in autophagosome
content results from a compromise in their clearance
by lysosomes and, consequently, from impaired rather
than enhanced macroautophagy. Systematic analysis of
autophagic ux, rather than autophagic markers, should
help to clarify these issues. However, independent of
this initial controversy, it has become clear that, as
described in the following sections, once in a disease
context interactions between autophagy and apoptosis
(or type I cell death) are complex and need to be anal-
ysed in the specic disorder or cell type [9496]. In
fact, autophagy and apoptosis share some molecular
components and appear to be in a delicate balance with
each other in most systems examined [97,98].
Pathology of autophagy
The broad array of physiological functions attributed
to autophagy justies why alterations in this catabolic
process lead to cellular malfunctioning and often cell
death, and has set the basis for its contribution to the
pathogenesis of severe human disorders. Rather than
providing an exhaustive list of disease conditions in
which autophagy has been shown to be altered, in
the following sections we have selected four common
pathological conditions, cancer, neurodegeneration,
heart dysfunction and immune and infectious diseases,
to comment on their interplay with the autophagic sys-
tem. The reason behind our selections is the fact that
in all of these pathologies growing evidence supports
a dual role of autophagy in their pathogenesis and dis-
ease progression, which leads to the question, Should
we inhibit or activate autophagy in these pathologies?.
Autophagy and cancer
Cancer was the rst human pathology connected
to autophagy through the discovery that Beclin1
(Atg6/VPS30 homologue), a core component of the
autophagosome nucleation complex, was monoalleli-
cally deleted in 4075% of sporadic human breast,
ovarian and prostate cancers [99]. Independent stud-
ies veried that heterozygous Beclin1
+/
mice develop
spontaneous tumours, including lymphomas, lung car-
cinomas, hepatocellular carcinomas and mammary pre-
cancerous lesions [100,101]. Analogous generation
of spontaneous hyperproliferating tumours was also
reported later upon deletion of other autophagy-related
genes, such as the ultraviolet resistance-associated
gene (UVRAG), the Bax interacting factor-1 (Bif-1)
and the LC3 (Atg8 homologue) processing protease
Atg4c [102104]. Furthermore, the products of com-
mon oncogenes, such as class I PI3K, PKB, TOR and
Bcl-2, have been shown to act as autophagy repres-
sors, whereas tumour suppressor gene products such
as p53, PTEN, DAPk and TSC1/TSC2 exert a stim-
ulatory effect on autophagy (reviewed in [3,98,105]).
Although, in light of this opposite effect of oncogenes
and tumour suppressors on autophagy, this process was
initially classied as an anti-oncogenic mechanism,
this conclusion has been challenged by experimen-
tal evidence supporting that under certain conditions
autophagy can also be pro-oncogenic (Figure 2).
From the perspective of cellular energetics, auto-
phagy is likely a pro-survival mechanism in both early
and late stages of cancer development, as it supplies
cells with the energy and essential macromolecules to
sustain normal cellular functions. However, it has been
proposed that in the early stages of cancer develop-
ment, quality control by autophagy, particularly over
genome maintenance, inhibits tumourigenesis, confer-
ring anti-oncogenic functions upon this pathway. In
addition, autophagy could also play a role in the main-
tenance or entry of cells into the G
0
phase and con-
sequently, prevent spontaneous hyperproliferation of
cells [106,107]. In contrast, in the late stages of onco-
genesis, autophagy is necessary for cancer survival,
as it contributes both energy for the rapidly dividing
cancer cells and quality control functions to eliminate
intracellular damage caused by the aggressive tumour
microenvironment and by anti-oncogenic interventions
(Figure 2). In fact, consistent with the pro-survival
function of autophagy, compromise of this pathway
(ie Beclin1 interference) in apoptosis-decient tumour
cells impairs their survival in metabolic stress condi-
tions in vitro and in vivo [108]. In general, blockage
of autophagy sensitizes cells to metabolic stress, often
leading to necrotic cell death accompanied by inam-
mation, a condition shown to promote tumourigene-
sis [109111]. Metabolic stress is intrinsic to rapidly
growing tumours, in which poor vascularization results
in lack of nutrients and oxygen for long periods of time
[112116]. Activation of macroautophagy under these
conditions has the potential to accommodate the acute
energy demands by providing cancer cells with amino
acids, free fatty acids and glucose, required to gener-
ate energy through the TCA cycle and via -oxidation
(Figure 2). Macroautophagy has also been recently
implicated in facilitating the unique utilization of glu-
cose by cancer cells, known as the Warburg effect
[117,118], by which cells favour glycolysis to accel-
erate ATP production and generate glycolysis inter-
mediates required for the transformed cells [119,120].
Blockage of autophagy has been shown to prevent Ras-
mediated oncogenic transformation by reducing glu-
cose uptake and its utilization toward glycolysis [121].
260 S Sridhar et al
Figure 2. Autophagy and cancer. Autophagy may play opposite roles in the oncogenic process. Anti-tumoural effect (left): active
maintenance of cellular quality control for cytosolic pro-oncogenic proteins such as p62 prevents malignant transformation of non-
tumoural cells. In addition, the supply of energy provided through macroautophagy activation reduces the dependence on glycolysis,
while assuring the energy required for maintenance of a stable genome, further preventing oncogenesis. Pro-oncogenic effect (right): the
reduction in macroautophagic activity in early stages of the oncogenic process favours malignant transformation, as the accumulation
of molecules such as p62 activates signalling mechanisms that promote necrosis and inammation. Poor quality control as a result of
diminished macroautophagy can also result in accumulation of defective mitochondria, with the subsequent release of harmful molecules
(cytochrome c and reactive oxygen species) that contribute to further altering genome maintenance. However, as the tumour progresses,
activation of macroautophagy is observed in many oncogenic processes, in part to compensate for the poor nutritional supply associated
with rapidly growing tumours and to defend cancer cells against damage induced by anti-oncogenic therapies. In addition, enhanced
mitochondrial degradation in this stage may contribute to the up-regulation of glycolysis to maintain the energetic balance (Warburg
effect) characteristic of malignant cells.
Although it is clear that interrupting glycolysis elimi-
nates the energetic advantage of the cancer cells and
compromises proliferation, the mechanism by which
autophagy up-regulates glycolysis is not known. It has
been proposed that this effect could in part be medi-
ated by activation of the removal of mitochondria via
autophagy (mitophagy) to force energy dependence on
glycolysis [119,120,122] (Figure 2). Autophagy could
impact oncogenic transformation in multiple ways; in
addition to the proposed effect on glycolysis, a better
maintenance of highly efcient mitochondria through
mitophagy has been recently proposed to also con-
tribute to meeting the energetic requirements of the
transforming cells [123]. Furthermore, an additional
factor in this already complex scenario is the possi-
ble impact that metabolic changes in the surrounding
stroma cells could have on the cancer cells. In fact,
an autophagy-dependent metabolic switch in the can-
cer stroma broblasts has been recently proposed. This
switch in the stroma could provide cancer cells with
glycolytic intermediates necessary for efcient ATP
production by oxidative phosphorylation [122].
Reduction in cellular energy upon autophagic com-
promise also decreases the delity of cellular pro-
cesses such as DNA replication and mitosis, result-
ing in genetic aberrations [124]. The occurrence of
these aberrations in tumour cells with defective qual-
ity control of organelles and toxic proteins due to the
autophagic compromise can precipitate death of the
cancer cells. In this respect, accumulation of the pro-
tein p62 (normally degraded by macroautophagy) when
this pathway is compromised leads to the formation
of p62 aggregates capable of stimulating inammation
by inhibition of nuclear factor-B (NF-B) and activa-
tion of NF-E2 related factor 2 (Nrf-2) [109,125,126]
(Figure 2).
Little is known to date about the contributions of
other forms of autophagy (CMA and microautophagy)
to cancer biology. Recent studies have revealed that
CMA contributes to the turnover of inactive forms of
the M2 isoform of pyruvate kinase, a key enzyme
in the maintenance of glycolysis in cancer cells
[127]. A number of additional glycolytic enzymes
have been recognized as CMA substrates, includ-
ing glyderaldehyde-3-phosphate dehydrogenase, phos-
phoglycerate kinase, aspartate aminotransferase and
aldolase B, strengthening the possible link between
CMA and the energetic balance of cancer cells
[49,128].
Collectively, the relationship between autophagy and
cancer has proved to be a very complex one. This dual
capability of autophagy to, on the one hand facilitate
tumour progression and, on the other hand diminish
malignant transformation, has reinforced the need to
critically evaluate autophagy in a disease-context and
stage-specic manner, especially during the design
of targeted therapy, as autophagy function is tightly
related to these factors [78,94].
Effectors and modulators of macroautophagy have
become attractive targets in the treatment of can-
cer. Autophagy up-regulation has been described in
many different types of cancers in response to anti-
oncogenic drugs, when it often exerts a protective
effect [129,130]. Based on these ndings, down-
regulation of autophagy should be an effective way of
enhancing the cytotoxic effect of different chemother-
apy protocols. In fact, inhibition of macroautophagy
has proved to be effective in enhancing the toxicity of
drugs commonly used in cancer therapy, such as oxalo-
platin [129] and the kinase inhibitors sorafenib [131],
epirubicin [132] or 5-uorouracil [133].
Different reports have also documented that the cyto-
toxic effect of some common anti-cancer agents is
in part due to their ability to up-regulate autophagy
[134138]. These ndings now raise a note of caution
in the universal applicability of autophagy inhibitors
as anti-cancer drugs. However, additional studies are
required to clarify the contribution of the observed
increase in autophagy in cancer cell death under these
conditions. Often, the proposed increase in autophagy
is based on the fact that levels of autophagy-related
proteins are higher during the treatment. Up-regulation
of autophagy markers does not necessarily mean
increased autophagic ux. In fact, if autophagy is func-
tioning properly, accumulation of autophagic compart-
ments rarely occurs. It is thus possible that the observed
increase in autophagic markers in some of these studies
is actually a reection of a compromise in the clear-
ance of autophagic compartments, rather than in their
formation. Accumulation of autophagolysosomes can
contribute to cell toxicity and be detrimental for the
affected cells. Interestingly, this toxic effect of the
congestion of the autophagic pathway is currently
being explored for therapeutic purposes. Although
some success has been obtained by directly targeting
the nal steps of autophagy, the lysosomal degrada-
tion, the characteristic plasticity of the lysosomal com-
partment makes a very prolonged inhibition necessary
before this intervention becomes detrimental. One way
around this problem, which is currently utilized in dif-
ferent clinical trials, is to combine the lysosomal block-
age with enhanced formation of autophagosomes (eg
by inhibition of the mTOR complex with rapamycin)
[139141]. The higher content of autophagic vacuoles,
as a result of both increased formation and reduced
clearance, can compromise cell viability by different
mechanisms. Accumulation of these compartments in
the cytoplasm interferes with intracellular trafcking
and prevents recycling of essential cellular compo-
nents (amino acids, free fatty acids, etc.). In addition,
as autophagolysosomes persist inside cells longer than
usual, their membranes often become leaky, facilitat-
ing the release of potent lysosomal enzymes in the
cytosol, further enhancing cellular damage and toxi-
city.
Autophagy and neurodegeneration
Maintenance of cellular homeostasis is essential in
neurons, a typical example of non-dividing differen-
tiated cells. The importance of autophagy in neuronal
homeostasis has now been well supported, despite orig-
inal disagreement on whether autophagy was active
in neurons. The reason for this contention was the
fact that autophagosomes, the morphological feature
of macroautophagy, were rarely observed in neurons.
However, recent studies support that this pathway is
constitutively active and that it can be further up-
regulated in neurons in response to very different stres-
sors [142144]. Perhaps the most conclusive support
for the existence of basal autophagy in neurons and for
its contribution to the maintenance of neuronal survival
came from studies in transgenic mouse models con-
ditionally knocked out for essential autophagy genes
in the central nervous system [68,69]. These animals,
even in the absence of any added stressor, displayed
marked neurodegeneration associated with the accumu-
lation of intracellular protein inclusions and neuronal
loss. The efcient capability of the lysosomal system
to remove newly formed autophagosomes could be
behind the low occurrence of detectable autophago-
somes in neurons in a given moment.
As with many other cells, neurons up-regulate
autophagy in response to common stressors but also
in defence against neuron-specic injuries, such as
axotomy, neuronal ischaemia or excitatory toxicity
[145147] (Figure 3). Often, failure to up-regulate
autophagy under these conditions or primary com-
promise of autophagic activity during the stress pre-
cipitates neuronal death post-injury [148]. However,
activation of autophagy in neurons may have a rela-
tively narrow window of opportunity, because recent
reports have revealed that genetic or chemical inhibi-
tion of autophagy becomes benecial at some specic
states post-injury [105]. These ndings suggest that
either excessive up-regulation of autophagy, or up-
regulation of this pathway under conditions in which
autophagosome formation or clearance cannot be guar-
anteed, may be harmful to neurons [149]. In further
support of the possible detrimental effect of massive
up-regulation of autophagy, recent studies have shown
that, under specic conditions, autophagosomes can
become a source of reactive oxygen species and thus
aggravate neurotoxicity [150].
Changes in autophagic activity have been described
in many protein conformational disorders, and among
them neurodegenerative diseases have received particu-
lar attention. The feature shared by all these conditions
is the presence of pathogenic proteins that accumulate
inside neurons, organized in the form of oligomeric
or multimeric structures. The disease originates from
262 S Sridhar et al
Figure 3. Autophagy and Neurodegeneration. (A) Protective autophagy: macroautophagy and CMA both contribute to the maintenance of
neuronal homeostasis and are necessary in the defence of neurons against injury and stressors. (B) Defective macroautophagy: defects in
macroautophagy have been described to occur at very different levels in neurodegenerative diseases. Some of the possible steps affected
in this process are highlighted in the model, and the conditions in which they have been observed are described in the text. (C) Defective
CMA: primary defects in CMA have been described both in Parkinsons disease and in certain tauopathies. While in the former condition,
pathogenic proteins such as -synuclein can block access of other cytosolic proteins to lysosomes via CMA by abnormally binding to the
translocation machinery, in tauopathies the accumulation at the surface of lysosomes of oligomeric forms of pathogenic tau targeted
via CMA destabilizes the lysosomal membrane and results in leakage of lysosomal enzymes into the cytosol, which often triggers cellular
death.
both the loss of function of the pathogenic protein and
the toxicity associated with the presence of the abnor-
mal protein structures, which often leads to neuronal
death. The rst connection between neurodegenera-
tion and autophagy originated from the observation
that protein aggregates can be eliminated by autophagy
[40,74] (Figure 3). In fact, pharmacological activation
of this catabolic process in experimental animal mod-
els of Huntingtons disease reduced cellular toxicity
and slowed down progression of the disease [151].
After these initial reports, the degradation of many
other pathogenic proteins by autophagy and the ben-
ecial effect of up-regulation of this pathway have
proved to be true in experimental models of many
other neurodegenerative conditions [152]. In fact, not
only the acute pharmacological activation of autophagy
but even chronic conditions that lead to a progressive
maintained up-regulation of this process, such as under
conditions when ER stress is maintained, have been
shown to have a positive effect [153]. These ndings
have now opened the possibility of utilizing modulators
of autophagy as the basis for therapeutic approaches for
these types of pathology and, in fact, ongoing chemi-
cal screenings aim at identifying chemical modulators
of this pathway with higher selectivity and potency
[154].
However, there are certain limitations to the uni-
versal use of up-regulation of macroautophagy for
anti-neurodegenerative purposes. In fact, it has been
reported that not all protein aggregates are recog-
nized by the macroautophagic machinery. Despite
the current dissection of molecules that participate
in autophagic recognition of aggregates (p62, NBR1
and several cytosolic chaperones, including hsc70 and
BAG-3), the presence of these proteins in an aggre-
gate, although necessary, does not seem to be suf-
cient for autophagic recognition. Thus, some protein
inclusions positive for these cargo-recognition proteins
remain unnoticed by the autophagic machinery, mak-
ing superuous any attempt to enhance autophago-
some formation as a way to eliminate these toxic
protein products [155]. Further studies are needed to
address whether expression of other cellular compo-
nents or specic post-translational modications in the
aggregated proteins could enhance their recognition by
the autophagic systems.
A second scenario, in which chemical up-regulation
of macroautophagy may not be effective against
neurodegeneration, is in those conditions in which
macroautophagy itself is compromised. Understanding
the macroautophagy step or steps defective in specic
neurodegenerative disorders is a priority if autophagy
enhancers are to be moved forward in the treatment of
these conditions. Examples of defects in almost all of
the steps of macroautophagy have been described in
different neurodegenerative disorders [66] (Figure 3).
For example, initiation of autophagy may be com-
promised because of altered signalling through the
insulin or mTOR pathways, which is tightly bound to
activation of autophagy. Also, conditions resulting in
lower content of available Atgs will reduce neuronal
autophagic capability, such as the recently described
depletion of LC3-II through abnormal interaction and
aggregation with p62 in the presence of dopaminergic
neurotoxin [156]. Along the same lines, abnormal inter-
action between mutant -synuclein (the protein that
accumulates in protein inclusions in Parkinsons dis-
ease) and Rab1 has been shown to misplace Atg9, a
protein required for the formation of autophagosomes,
out of the ER membrane [157]. Under other conditions,
problems arise at the level of cargo recognition, either
because of alterations in the organelle-specic mark-
ers for degradation or in the autophagic machinery. A
primary defect at the level of the limiting membrane
that seems to prevent selective recognition of cargo has
been recently described in cellular and animal models
of Huntingtons disease [158]. In these cases, mutant
huntingtin binds tightly to the inner surface of the form-
ing autophagosome, resulting in an abnormally high
interaction with p62 in this compartment that affects its
ability to bind cargo. In other conditions, autophago-
somes form and sequester the pertinent cargo but they
fail to be cleared from the cytosol. Problems with
clearance could result from alterations at very differ-
ent levels. For example, problems with vesicular traf-
cking could indirectly interfere with the mobilization
of autophagosomes toward the lysosomal compartment
[159]. Pathogenic proteins can also interfere with the
fusion step, which, although still not completely elu-
cidated at the molecular level, is known to depend
on different SNARE proteins, the actin cytoskeleton
and the histone deacetylase 6 (HDAC6) [160]. Con-
sequently, changes in any of these components could
lead to intracellular accumulation of autophagosomes.
Lastly, primary defects in the lysosomal compartment
also have a negative impact on clearance of autophago-
somes in different neurological disorders. The rea-
sons for lysosomal failure could be multiple. In prin-
ciple, most lysosomal storage disorders could com-
promise autophagosome clearance because often the
accumulation of the undegraded product inside lyso-
somes limits their degradative capacity [161]. In addi-
tion, other conditions that alter lysosomal membrane
stability, decrease lysosomal biogenesis or change lyso-
somal pH could also alter autophagosome clearance.
In fact, defective acidication of lysosomes, because
of compromised targeting of a component of the pro-
ton pump from the ER to the lysosomal membrane,
has been already identied as causative of the reduced
rates of autophagy in some models of Alzheimers
disease [162]. As functional analysis of autophagy
becomes more broadly utilized in the study of neurode-
generative diseases, it is likely that new connections
between these pathologies and autophagy will become
evident.
Alterations of CMA have also been described in
some neurodegenerative disorders (Figure 3). Although
in many of them, this pathway becomes up-regulated
as a consequence of the failure in macroautophagy, dif-
ferent pathogenic proteins have been shown to directly
interfere with CMA activity [163]. Mutant forms of -
synuclein can be targeted to lysosomes via CMA but,
in contrast to the wild-type protein that binds to the
lysosomal receptor and rapidly reaches the lumen for
degradation, the mutant variants fail to translocate. Per-
sistence of mutant -synuclein tightly bound to the
CMA receptor at the lysosomal membrane inhibits
lysosomal degradation of other cytosolic proteins
via this pathway [164]. A similar effect was later
described for wild-type -synuclein upon modication
by dopamine, which makes CMA blockage relevant for
sporadic forms of Parkinsons disease, more common
than the familial forms [165]. Later studies have also
proposed interference of CMA by other Parkinsons
disease-related proteins, such as mutant forms of UCH-
L1 [166]. A higher degree of lysosomal compromise as
a result of lysosomal targeting of pathogenic proteins
via CMA has been described in certain tauopathies,
where the mutant forms of the protein not only interact
abnormally with CMA components blocking this path-
way, but also disrupt the lysosomal membrane as they
organize into toxic oligomeric species on their surface
[167].
To date, systematic studies analysing the contribu-
tion of alterations in microautophagy to neurodegen-
eration have not been performed. However, the fact
that protein unfolding is not a prerequisite for microau-
tophagy makes attractive the possibility that micro-
aggregates can be delivered to this pathway for degra-
dation.
Growing evidence supports that neurons utilize
diverse ways to eliminate pathogenic proteins and that
multiple steps of the autophagic process are often
affected in a given neurodegenerative disorder. Thus,
for example, in the case of Alzheimers disease (AD),
macroautophagy contributes to the elimination of the
toxic product of the amyloid precursor protein (APP)
A-. However, clearance of A- is compromised as the
disease progresses, due to the failure in this autophagic
pathway [168]. In most forms of AD, the autophagic
defect occurs in the late steps of macroautophagy.
Thus, autophagosomes form properly sequestering the
usual cargo but they are not eliminated through the
264 S Sridhar et al
lysosomal system [168]. As described above, decient
acidication of the lysosomal lumen, due to the inabil-
ity to target to lysosomes one of the subunits of the
proton pump that usually acidies this compartment,
has been recently described in some types of AD [169].
Persistence of autophagosomes in AD neurons is par-
ticularly toxic because the enzymes responsible for
processing of APP into A- as well as APP accumu-
late in these compartments. Autophagosomes become
in this case a new site of intracellular production of
toxic A- [168]. Failure of the autophagic system com-
promises the elimination of aggregate forms of tau, a
protein that also accumulates in AD neurons. In fact,
for certain types of tau mutations, this pathogenic pro-
tein could contribute to the failure of macroautophagy,
due to the toxic effect that the still soluble forms of
the protein exert in the membrane of lysosomes when
they are delivered to this compartment by CMA [167].
Similarly, in the case of Parkinsons disease (PD)
the most common pathogenic protein, -synuclein, is
usually degraded by different autophagic and non-
autophagic pathways. Soluble forms of the protein
are substrates of both the ubiquitin proteasome sys-
tem and of CMA [164,170]. However, macroautophagy
is the only plausible way for the elimination of the
pathogenic variants of this protein once they aggregate
[171]. As in the other disorders, pathogenic forms of -
synuclein interfere with the normal functioning of the
ubiquitin proteasome pathway [170], CMA [164,165]
and even macroautophagy at the level of autophago-
some formation [157]. The recently identied physio-
logical role for Parkin, a protein also related to PD,
in mitophagy, suggests that alterations of this selec-
tive form of autophagy could also contribute to the
pathogenesis of this disease [172].
Macroautophagy has proved to be an effective mech-
anism for the degradation of aggregates of huntingtin,
the protein mutated in Huntingtons disease (HD)
and main component of the inclusions observed in
the affected neurons [151,173]. Huntingtin is a very
dynamic protein that undergoes physiological cleavage
into different functional fragments that likely are turned
over by different proteolytic systems. Mutant hunt-
ingtin, even before aggregation, seems to be primarily a
target for macroautophagic degradation [174], although
specic posttranslational modications can also favour
its elimination by CMA [175]. As in the other neu-
rodegenerative disorders, growing evidence supports
a direct toxic effect of the mutant protein on the
autophagic system. For example, mutant huntingtin has
been described to accumulate on the luminal side of the
limiting membrane as the autophagosome forms and
thus interfere with the recognition of cytosolic cargo,
including huntingtin protein aggregates [158]. Alter-
ations at the level of autophagosome trafcking and
clearance have also been described in some experimen-
tal models of HD [176]. Although huntingtin bears sev-
eral CMA-targeting motifs in its amino acid sequence,
the contribution of this pathway to the removal of the
pathogenic protein is, overall, modest. However, recent
studies support a benecial effect of the articial tar-
geting of mutant huntingtin for CMA degradation that
could be explored for therapeutic purposes [177].
It is anticipated that a similar dual interaction of
different pathogenic proteins with the autophagic sys-
temsby which they can be eliminated through these
pathways but also interfere with their normal function-
ingcould also contribute to pathogenesis in other
neurodegenerative disorders.
Autophagy and the failing heart
The heart is comprised of long-lived, post-mitotic cells
with little regenerative capacity, which are continu-
ally subjected to stress, such as ischaemia, pressure
overload and ischaemiareperfusion injury. Adapta-
tion to these conditions is attained through remodelling
(myocytes elongate and undergo hypertrophy) and fail-
ure to do so frequently constitutes the basis of coronary
artery disease, hypertension and congestive heart fail-
ure [178,179]. Evidence for the role of basal autophagy
in the quality control and housekeeping of cardiomy-
ocytes was rst obtained through genetic models of
LAMP-2 knock-out mice (defective for autophago-
somelysosome fusion) that demonstrated cardiomy-
opathy and abnormal accumulation of autophagic
vacuoles, similar to that observed in Danons disease
patients [180,181]. In fact, mutations in the LAMP-
2 gene were subsequently described in these patients
[182]. Studies in cardiomyocyte-specic Atg5 and Atg7
knock-out models have reiterated the need for func-
tional autophagy to preserve normal cardiac function,
both under basal conditions and in response to stress
[183]. In fact, pronounced loss of autophagy in car-
diomyocytes with age seems to be behind different
forms of age-related cardiomyopathy [184].
Added to the key role of basal macroautophagy
in cardiomyocyte homeostasis, growing evidence also
supports an important contribution of this pathway
in the heart in response to stressors. As described
in the brain, macroautophagy has also proved to
be essential for the prevention of cardiomyocyte
proteinopathies, such as those arising from desmin
and --crystallin accumulation [185,186]. Autophagy
induced in response to cardiac stress (especially during
ischaemiareperfusion injury) also plays a cytopro-
tective role in the heart. In fact, in support of this
prosurvival function, different studies have demon-
strated that pharmacological inhibition of autophagy
during mild ischaemic stress enhances cardiomyocyte
death [187,188], whereas macroautophagy activation
is cardioprotective [189,190]. The benecial effect of
macroautophagy up-regulation under these conditions
could result, in part, from an efcient removal of
the mitochondrial population compromised under these
conditions. Thus, mitochondrial membrane depolar-
ization and increased production of reactive oxygen
species by mitochondria are common features asso-
ciated to ischaemiareperfusion. Degradation of the
altered mitochondria by macroautophagy under these
conditions has been shown to efciently ameliorate
cellular damage by reducing the activation of pro-
apoptotic cascades [191193].
However, induction of macroautophagy in the
stressed heart can also be detrimental and contribute
to heart failure, judging by the fact that pharmacolog-
ical or genetic blockage of macroautophagy enhances
cell survival post-ischaemiareperfusion injury in spe-
cic settings [194]. The timing and the nature of the
condition that induced cardiac stress may be essential
for the switch in the effect of macroautophagy. Thus,
some studies suggest that macroautophagy is cardio-
protective during ischaemic recovery but maladaptive
during reperfusion recovery [195]. It is possible that,
during reperfusion, the need for removal of dysfunc-
tional mitochondria and oxidatively damaged cellular
structures that accumulated during the ischaemic period
could drive the autophagic response to be more aggres-
sive than desired, resulting in cell death. In fact, genetic
up-regulation of autophagy in response to the haemo-
dynamic stress-induced hypertrophic growth response
has also proved to be maladaptive and to result in
pathological cardiac hypertrophy [196].
In summary, as in the case of tumour biology
and neurodegeneration, the role of autophagy in heart
pathology is also context-dependent and excessive or
insufcient macroautophagy is often associated with
disease. However, when maintained under strict con-
trol, up-regulation of macroautophagy by compounds
such as resveratrol has proved to be a useful cardiopro-
tective strategy during ischaemiareperfusion injury
[197199].
Although the heart is one of the organs in which
CMA is up-regulated most rapidly in response to star-
vation [200], the contribution of CMA to cardiomy-
ocyte homeostasis and to heart pathology has not been
explored in depth. As mentioned above, mutations in
LAMP-2 occur in patients with Danons cardiomyopa-
thy, but the phenotype seems, for the most part, to be
related to the presence of large autophagic vacuoles
in muscle, reective of compromised macroautophagy.
This could be explained by the fact that the lamp2 gene
undergoes splicing, giving rise to three protein variants,
A, B and C [201] and that mutations in only the B vari-
ant, tightly related to macroautophagy, are enough to
reproduce the full vacuolar phenotype [182], whereas
changes in LAMP-2A, the variant required for CMA,
do not affect macroautophagy [202].
Autophagy, infectious disorders and autoimmunity
The autophagy machinery can act as a cell-autonomous
defence against invading pathogens through a process
known as xenophagy [203]. Activation of this process
has been extensively reported, for example, in response
to Group A Streptococcus infection in epithelial cells
(Figure 4). The fact that Atg5 deciency allows bacte-
ria to survive and multiply robustly supports the normal
contribution of autophagy in the elimination of this
pathogen [204]. Autophagic surveillance is not limited
to bacteria as, in fact, a protective role for autophagy
has been also demonstrated for the vesicular stomatitis
virus, herpes simplex virus 1 or HIV-1, among others
[205207].
Cytosolic autophagy often becomes a second surveil-
lance point for pathogens such as Listeria monocy-
togenes that can escape phagosomes by puncturing
their membrane to replicate in the cytoplasm. How-
ever, once in the cytoplasm, the autophagic surveil-
lance mechanism is activated to entrap the escaped
bacteria and deliver them to endocytic and lysoso-
mal compartments for degradation [208]. Pathogens
that survive inside vesicular compartments can also be
controlled by macroautophagy. For example, Mycobac-
terium tuberculosis resides in phagosomes by avoiding
their fusion to lysosomes. Interestingly, this blockage
can be overcome by induction of autophagy, leading to
the degradation of this pathogen [209].
Autophagy proteins may also help to accelerate
phagosome maturation through a process that has been
termed LC3-associated phagocytosis. Engagement of
toll-like receptors has been shown to induce recruit-
ment of LC3 to the phagosomal membrane and favour
fusion with the lysosome [210].
Despite this active involvement of autophagy in
pathogen elimination, some pathogens have evolved
to take advantage of the different compartments of
the autophagy pathway to establish replicative niches
[211,212] (Figure 4). Evidence that the autophagosome
compartment is required for the replication of cer-
tain pathogens, such as Porphyromonas gingivalis or
Coxiella burnetti was provided by demonstrating that
treatment with 3-methyladenine, a well-characterized
inhibitor of autophagosome formation, was efcient in
decreasing the survival of these pathogens [213,214].
In fact, some of these microorganisms that utilize com-
partments of the autophagic system have developed
mechanisms to expand the size and number of these
compartments. For example, Staphylococcus aureus is
capable of secreting a factor that activates autophagy
[215]. Seclusion inside the autophagosomes may be
benecial for pathogens as a way to escape the cytoso-
lic surveillance mechanisms, but these compartments
may also contain cytosolic materials that can be uti-
lized as an energy source by the microorganisms.
This bivalent role of autophagy in pathogen defence
suggests that, although it should be possible to phar-
macologically manipulate the autophagic system to
eliminate different pathogens, it is essential to rst
understand the characteristics of the pathogen
autophagy interaction in each of the individual
instances [216,217].
Apart from its role in cell-autonomous immunity,
autophagy plays a role in activation of adaptive
immunity through its recently described involvement
in antigen processing and presentation to lympho-
cytes [218220] (Figure 4). In professional APCs,
phagosome-processed extracellular antigens are pre-
sented through MHC class II molecules to CD4 T
266 S Sridhar et al
Figure 4. Autophagy and the immune system. (A) Macroautophagy against pathogens: macroautophagy contributes to the elimination of
different types of pathogensbacteria and viruseswhen they escape to the cytosol after internalization in the phagosome. Under certain
conditions, fusion of autophagosomes with phagosomes is required before degradation can occur. (B) Pathogens using macroautophagy:
growing evidence supports that certain pathogens have evolved to utilize autophagosomes as a site of replication and can actively
prevent the fusion of this compartment, with lysosomes to guarantee their survival. (C) Antigen presentation: all three forms of autophagy,
macroautophagy, CMA and microautophagy have been shown to contribute to antigen loading of MHC class II molecules for presentation
of antigens to activate T cells.
cells. However, several cytosolic and nuclear pro-
teins have been found associated with MHC II
molecules [221,222]. In fact, pharmacological inhibi-
tion of macroautophagy has been shown to be efcient
in reducing MHC class II intracellular antigen pre-
sentation [223225], whereas activation of autophagy
promotes this type of presentation [226]. Later stud-
ies have conrmed the presence of intracellular anti-
gens in autophagosomes, and marked reduction of
MHC II presentation in lymphoblastoid cell lines upon
knock-down of essential Atgs, as well as in vivo in
Atg5-decient dendritic cells [227,228]. Interestingly,
presentation of self-antigens by class II molecules is
not limited to macroautophagy but may also involve
other types of autophagy. In fact, over-expression of
LAMP-2A, the receptor for CMA, has been shown to
enhance MHC II presentation of intracellular antigens
[229], and a new microautophagy-dependent process
of antigen delivery into late endosomes in dendritic
cells has also been recently characterized [31]. Fur-
thermore, participation of autophagy in antigen pre-
sentation may not be limited to presentation through
MHC II. Although it is traditionally accepted that MHC
class I presents intracellular antigens processed through
the proteasomal pathway, growing evidence supports
that macroautophagy could also assist in MHC I
presentation by collaborating with the proteasome in
the processing of intracellular proteins [230,231].
Also of interest is the recently proposed contribution
of autophagy in the establishment of tolerance to self
antigens. Self-reactive T cells are usually actively elim-
inated through MHC class II presentation in epithelial
cells of the thymus to allow T cell tolerance to self-
antigens [232]. Proof that autophagy regulates central
T cell tolerance has been provided by a recent study
showing that transplantation into athymic nude hosts
of Atg5-decient thymus results in defects in posi-
tive and negative selection and the development of
autoimmunity [233]. Interestingly, the antigen-loading
compartments for MHC class II in immature dendritic
cells, which are involved in peripheral tolerance, con-
tinuously receive input from autophagosomes [234].
Furthermore, genetic polymorphisms in two different
autophagy genes (ATG16L1 and IRGM) have been
linked to Crohns disease [235,236]. Compromised
autophagic function may result in insufcient induc-
tion of tolerance against commensals or self-antigens
in the gut, [235,236], although it may also affect the
secretion of antimicrobial proteins by Paneth cells [7].
This novel role of autophagy in the establishment
and maintenance of tolerance also suggests a possi-
ble role for autophagy in autoimmunity [237]. In this
respect, autophagy is known to contribute to apoptotic-
cell clearance [238], and defective clearance of apop-
totic cells has been proposed to lead to autoimmune
diseases, such as systemic lupus erythematosus [239].
As any other cell type, cells of the immune system
also depend on autophagy for the maintenance of their
homeostasis [240], but changes in autophagy in T cells
in particular have also been described to contribute to
modulation of specic cell functions. Thus, the activa-
tion of macroautophagy observed upon T cell activa-
tion is required to promote T cell differentiation and
survival and allows cells to accommodate the bioener-
getic requirements of these conditions [241243].
Overall, recent studies support that autophagy
defends the cell in a bimodal fashion; rst, it directly
eliminates invading pathogens [244]; and second, it
simultaneously assists the immune system of the host
organism to mount a specialized immune response
against the invader by processing pathogenic anti-
gens for presentation to T cells [6,203,245]. Therefore
autophagy can be envisaged as an immediate as well
as a persistent mechanism of cellular defence.
Conclusions and future perspectives
The better molecular characterizations of the differ-
ent autophagic pathways, as well as the possibility
of genetically manipulating these cellular processes,
have helped to establish tight connections between
autophagic malfunctioning and disease. The initial
excitement about the possibility of modulating auto-
phagy with therapeutic purposes in different disorders
has been followed by some degree of confusion as
to whether autophagy should be up- or down-regulate
in these conditions. As described in this review, both
up- and down-regulation of macroautophagy have been
shown to be protective against cancer, neurodegener-
ation, infectious diseases and ischaemic insult in the
heart. How to decide what to do? Further analysis in
most of these conditions is required to fully under-
stand the contribution of autophagic malfunctioning to
the disease. Questions, such as when in the course of
the disease autophagic function becomes compromised,
what changes in each autophagic pathway and whether
these changes are primary or compensatory to failure in
other systems, need to be answered before autophagy
modulators can be systematically used in the treatment
of these conditions.
A considerable advance in this respect has been
the introduction of functional read-outs of autophagy
to complement the initial morphological analysis.
For example, the presence of a higher number of
autophagosomes in many disease conditions, initially
interpreted as an increase in macroautophagy, is now
more cautiously analysed, because blockage in the late
steps of this pathway can also have a similar mor-
phological signature. Thus, conditions initially labelled
as having too much autophagy are being currently
revised as having a blockage in autophagic clearance.
Blocking autophagosome formation may only be ben-
ecial then, when excessive autophagosome content
and autophagic clogging contribute to the pathology,
but not when autophagy is up-regulated in the disease
to compensate for failure in other systems. Along the
same lines, the ultimate goal may not be to repress
autophagosome formation in some of these cases, but
instead to facilitate their clearance by directly repair-
ing possible defects in the late steps of the autophagic
process.
In addition to determining the right timing for mod-
ulating autophagy in many of these diseases, and
whether this process should be up- or down-regulated,
further expansion of the chemical options to manip-
ulate autophagy is needed for it to become a routine
therapeutic target. To date, most of the macroautophagy
inhibitors used in clinical trials act during the late steps
of this process, on the lysosomal compartment, which
is also shared by other autophagic pathways. In con-
trast, for activators, most of the available drugs have
an effect on initiation and autophagosome formation,
but few compounds have been shown to be effective at
increasing the overall autophagic ux. Ongoing chem-
ical screenings are currently addressing the need for
these types of modulators and should render usable
molecules in a timely fashion [154].
Acknowledgment
We thank Dr Susmita Kaushik for critically review-
ing the manuscript. Work in our laboratories is sup-
ported by the National Institutes of Health/National
Institute on Aging (Grant Nos. AG021904 to AMC
and AG031782 to AMC and FM) and the National
Institute of Allergy and Infectious Diseases (Grant
No. AI059738 to FM). AMC is also supported by a
Hirschl/Weill Caulier Career Scientist Award.
Authors contributions
All authors contributed separate sections to this review
and all read and edited the nal submitted version.
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