Apoptosis-inducing factor 2 (AIFM2), also known as apoptosis-inducing factor-homologous mitochondrion-associated inducer of death (AMID), is a protein that in humans is encoded by the AIFM2 gene, also known as p53-responsive gene 3 (PRG3), on chromosome 10.[5][6][7][8]
| AIFM2 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Aliases | AIFM2, AMID, PRG3, apoptosis inducing factor, mitochondria associated 2, apoptosis inducing factor mitochondria associated 2, FSP1 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 605159; MGI: 1918611; HomoloGene: 6862; GeneCards: AIFM2; OMA:AIFM2 - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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This gene encodes a flavoprotein oxidoreductase that binds single stranded DNA and is thought to contribute to apoptosis in the presence of bacterial and viral DNA. The expression of this gene is also found to be induced by tumor suppressor protein p53 in colon cancer cells.[8][9]
Structure
AIFM2 can be found only both in prokaryotes and eukaryotes.[6][7][10][11] Sequence analysis reveals that the AIFM2 gene promoter contains a consensus transcription initiator sequence instead of a TATA box.[11] Though AIFM2 also lacks a recognizable mitochondrial localization sequence and cannot enter the mitochondria, it is found to adhere to the outer mitochondrial membrane (OMM), where it forms a ring-like structure.[6][5][7][11][9] Two deletion mutations at the C-terminal (aa 1–185 and 1–300) result in nuclear localization and failure to effect cell death, suggesting that AIFM2 must be associated with the mitochondria in order to induce apoptosis. Moreover, domain mapping experiments reveal that only the C-terminal 187 aa is required for apoptotic induction.[6] Meanwhile, mutations in the N-terminal putative FAD- and ADP-binding domains, which are responsible for its oxidoreductase function, do not affect its apoptotic function, thus indicating that these two functions operate independently.[7][5] It assembles stoichiometrically and noncovalently with 6-hydroxy-FAD.[7]
The AIFM2 gene contains a putative p53-binding element in intron 5, suggesting that its gene expression can be activated by p53.[5][7][11]
Function
This protein is a flavoprotein that functions as an NAD(P)H-dependent oxidoreductase and induces caspase- and p53-independent apoptosis.[6][5][7] The exact mechanisms remain unknown, but AIFM2 is found to localize to the cytosol and the OMM. Thus, it may carry out this function by disrupting mitochondrial morphology and releasing proapoptotic factors.[6] Also, under conditions of stress which activate p53-mediated apoptosis, such as hypoxia, AIMF2 may stabilize p53 by inhibiting its degradation and accelerate the apoptotic process. Under normal conditions (i.e., undetectable p53 expression), the AIMF2 gene is highly expressed in the heart, followed by liver and skeletal muscle, with low levels detected in the placenta, lung, kidney, and pancreas and the lowest in the brain. However, in organs such as the heart, there may be additional regulatory mechanisms to suppress its proapoptotic function.[5] For instance, AIFM2 may be able to directly bind nuclear DNA and effect chromatin condensation, as with AIF.[7] Furthermore, AIMF2 expressed at low levels may function as an oxidoreductase involved in metabolism.[5] Hence, under normal cellular conditions, AIFM2 may promote cell survival rather than death by metabolic processes such as generating reactive oxygen species (ROS) to maintain survival signaling.[9]
Clinical Significance
AIFM2 has been implicated in tumorigenesis as a p53-inducible gene.[11] AIFM2 mRNA levels are observed to be downregulated in many human cancer tissues, though a previous study reported that AIFM2 mRNA transcripts were only detected in colon cancer and B-cell lymphoma cell lines.[6][7] Furthermore, its DNA-binding ability contributes to its involvement in the apoptosis-inducing response to viral and bacterial infections, possibly through its role in ROS regulation.[11]
Evolution
The phylogenetic studies indicates that the divergence of the AIFM1 and other AIFs occurred before the divergence of eukaryotes.[10]
Interactions
AIFM2 is shown to interact with p53.[5]
AIFM2 is not inhibited by Bcl-2.[5]
AIFM2 can also bind the following coenzymes:
- 6-hydroxy-FAD,[7]
- Flavin adenine dinucleotide (FAD),[7]
- NADPH/NADP+,[7]
- NADH/NAD+,[7] and
- pyridine nucleotide coenzyme.[7]
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000042286 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000020085 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ a b c d e f g h i Ohiro Y, Garkavtsev I, Kobayashi S, Sreekumar KR, Nantz R, Higashikubo BT, Duffy SL, Higashikubo R, Usheva A, Gius D, Kley N, Horikoshi N (Jul 2002). "A novel p53-inducible apoptogenic gene, PRG3, encodes a homologue of the apoptosis-inducing factor (AIF)". FEBS Lett. 524 (1–3): 163–71. doi:10.1016/S0014-5793(02)03049-1. PMID 12135761.
- ^ a b c d e f g Wu M, Xu LG, Li X, Zhai Z, Shu HB (Jul 2002). "AMID, an apoptosis-inducing factor-homologous mitochondrion-associated protein, induces caspase-independent apoptosis". J Biol Chem. 277 (28): 25617–23. doi:10.1074/jbc.M202285200. PMID 11980907.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ a b c d e f g h i j k l m n Marshall KR, Gong M, Wodke L, Lamb JH, Jones DJ, Farmer PB, Scrutton NS, Munro AW (Aug 2005). "The human apoptosis-inducing protein AMID is an oxidoreductase with a modified flavin cofactor and DNA binding activity". J Biol Chem. 280 (35): 30735–40. doi:10.1074/jbc.M414018200. PMID 15958387.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ a b "Entrez Gene: AIFM2 apoptosis-inducing factor, mitochondrion-associated, 2".
- ^ a b c Gong, M; Hay, S; Marshall, KR; Munro, AW; Scrutton, NS (12 October 2007). "DNA binding suppresses human AIF-M2 activity and provides a connection between redox chemistry, reactive oxygen species, and apoptosis". The Journal of Biological Chemistry. 282 (41): 30331–40. doi:10.1074/jbc.m703713200. PMID 17711848.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ a b Klim, Joanna; Gładki, Arkadiusz; Kucharczyk, Roza; Zielenkiewicz, Urszula; Kaczanowski, Szymon (2018-04-27). "Ancestral State Reconstruction of the Apoptosis Machinery in the Common Ancestor of Eukaryotes". G3: Genes|Genomes|Genetics. 8 (6): 2121–2134. doi:10.1534/g3.118.200295. ISSN 2160-1836. PMC 5982838. PMID 29703784.
- ^ a b c d e f Wu, M; Xu, LG; Su, T; Tian, Y; Zhai, Z; Shu, HB (2 September 2004). "AMID is a p53-inducible gene downregulated in tumors". Oncogene. 23 (40): 6815–9. doi:10.1038/sj.onc.1207909. PMID 15273740.
External links
- Human AIFM2 genome location and AIFM2 gene details page in the UCSC Genome Browser.
- Human PRG3 genome location and PRG3 gene details page in the UCSC Genome Browser.