AIFM2

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
Identifiers
AliasesAIFM2, AMID, PRG3, apoptosis inducing factor, mitochondria associated 2, apoptosis inducing factor mitochondria associated 2, FSP1
External IDsOMIM: 605159 MGI: 1918611 HomoloGene: 6862 GeneCards: AIFM2
Gene location (Human)
Chr.Chromosome 10 (human)[1]
Band10q22.1Start70,098,223 bp[1]
End70,132,934 bp[1]
Orthologs
SpeciesHumanMouse
Entrez

84883

71361

Ensembl

ENSG00000042286

ENSMUSG00000020085

UniProt

Q9BRQ8

Q8BUE4

RefSeq (mRNA)

NM_032797
NM_001198696

NM_001039194
NM_001284300
NM_153779
NM_178058

RefSeq (protein)

NP_001185625
NP_116186

NP_001034283
NP_001271229
NP_722474
NP_835159

Location (UCSC)Chr 10: 70.1 – 70.13 MbChr 10: 61.72 – 61.74 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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]

Function

The protein encoded by this gene has significant homology to NADH oxidoreductases and the apoptosis-inducing factor PDCD8/AIF. Overexpression of this gene has been shown to induce apoptosis. The expression of this gene is found to be induced by tumor suppressor protein p53 in colon cancer cells.[8]

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 N-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:

References
  1. GRCh38: Ensembl release 89: ENSG00000042286 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000020085 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Ohiro Y, Garkavtsev I, Kobayashi S, Sreekumar KR, Nantz R, Higashikubo BT, Duffy SL, Higashikubo R, Usheva A, Gius D, Kley N, Horikoshi N (July 2002). "A novel p53-inducible apoptogenic gene, PRG3, encodes a homologue of the apoptosis-inducing factor (AIF)". FEBS Letters. 524 (1–3): 163–71. doi:10.1016/S0014-5793(02)03049-1. PMID 12135761. S2CID 6972218.
  6. Wu M, Xu LG, Li X, Zhai Z, Shu HB (July 2002). "AMID, an apoptosis-inducing factor-homologous mitochondrion-associated protein, induces caspase-independent apoptosis". The Journal of Biological Chemistry. 277 (28): 25617–23. doi:10.1074/jbc.M202285200. PMID 11980907.
  7. Marshall KR, Gong M, Wodke L, Lamb JH, Jones DJ, Farmer PB, Scrutton NS, Munro AW (September 2005). "The human apoptosis-inducing protein AMID is an oxidoreductase with a modified flavin cofactor and DNA binding activity". The Journal of Biological Chemistry. 280 (35): 30735–40. doi:10.1074/jbc.M414018200. PMID 15958387.
  8. "Entrez Gene: AIFM2 apoptosis-inducing factor, mitochondrion-associated, 2".
  9. Gong M, Hay S, Marshall KR, Munro AW, Scrutton NS (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.
  10. Klim J, Gładki A, Kucharczyk R, Zielenkiewicz U, Kaczanowski S (May 2018). "Ancestral State Reconstruction of the Apoptosis Machinery in the Common Ancestor of Eukaryotes". G3. 8 (6): 2121–2134. doi:10.1534/g3.118.200295. PMC 5982838. PMID 29703784.
  11. Wu M, Xu LG, Su T, Tian Y, Zhai Z, Shu HB (September 2004). "AMID is a p53-inducible gene downregulated in tumors". Oncogene. 23 (40): 6815–9. doi:10.1038/sj.onc.1207909. PMID 15273740.

Further reading
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