Apoptosis-inducing factor 2 (AIFM2), also known as ferroptosis suppressor protein 1 (FSP1), 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][9][10]
| 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 | ||||||||||||||||||||||||||||||||||||||||||||||||||
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This gene encodes a flavoprotein oxidoreductase that reduces coenzyme Q10, vitamin E, and vitamin K.
Function edit
The AIFM2 gene encodes the FSP1 protein encoded by this gene has significant homology to NADH oxidoreductases and the apoptosis-inducing factor PDCD8/AIF. Although it was originally proposed that this protein induce apoptosis due to its similarity with AIF, findings from James Olzmann's group at UC Berkeley [10] and Marcus Conrad's group at the Helmholtz Institute [9] demonstrated that the primary cellular function of FSP1 is to suppress lipid peroxidation and the induction of the regulated, non-apoptotic cell death pathway known as ferroptosis. Mechanistically, FSP1 reduces oxidized coenzyme Q10 (i.e., ubiquinone) to its reduced form (i.e., ubiquinol), which functions as an excellent lipophilic antioxidant to prevent the propagation of lipid peroxidation.[9][10] FSP1 also may act through the reduction of other molecules, such as vitamin E and vitamin K.
Structure edit
AIFM2 can be found only both in prokaryotes and eukaryotes.[6][7][11][12] Sequence analysis reveals that the AIFM2 gene promoter contains a consensus transcription initiator sequence instead of a TATA box.[12] 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][12][13] 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][12]
Function edit
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 AIFM2 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.[13]
Clinical significance edit
AIFM2 has been implicated in tumorigenesis as a p53-inducible gene.[12] 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.[12]
Inhibitors[9][14] of FSP1 have been identified to induce ferroptosis. icFSP1 has been shown to cause dissociation of FSP1 from the membrane and phase separation of FSP1 into droplets.
Evolution edit
The phylogenetic studies indicates that the divergence of the AIFM1 and other AIFs occurred before the divergence of eukaryotes.[11]
Interactions edit
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 edit
- ^ 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 (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.
- ^ a b c d e f g 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.
- ^ 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 (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.
- ^ "Entrez Gene: AIFM2 apoptosis-inducing factor, mitochondrion-associated, 2".
- ^ a b c d Doll S, Freitas FP, Shah R, Aldrovandi M, da Silva MC, Ingold I, et al. (November 2019). "FSP1 is a glutathione-independent ferroptosis suppressor". Nature. 575 (7784): 693–698. Bibcode:2019Natur.575..693D. doi:10.1038/s41586-019-1707-0. hdl:10044/1/75345. PMID 31634899. S2CID 204833583.
- ^ a b c Bersuker K, Hendricks JM, Li Z, Magtanong L, Ford B, Tang PH, et al. (November 2019). "The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis". Nature. 575 (7784): 688–692. Bibcode:2019Natur.575..688B. doi:10.1038/s41586-019-1705-2. PMC 6883167. PMID 31634900.
- ^ a b 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.
- ^ a b c d e f 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. S2CID 8541615.
- ^ a b 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.
- ^ Nakamura T, Hipp C, Santos Dias Mourão A, Borggräfe J, Aldrovandi M, Henkelmann B, Wanninger J, Mishima E, Lytton E, Emler D, Proneth B, Sattler M, Conrad M (July 2023). "Phase separation of FSP1 promotes ferroptosis". Nature. 619 (7969): 371–377. Bibcode:2023Natur.619..371N. doi:10.1038/s41586-023-06255-6. ISSN 1476-4687. PMC 10338336. PMID 37380771.
Further reading edit
- Horikoshi N, Cong J, Kley N, Shenk T (August 1999). "Isolation of differentially expressed cDNAs from p53-dependent apoptotic cells: activation of the human homologue of the Drosophila peroxidasin gene". Biochemical and Biophysical Research Communications. 261 (3): 864–9. doi:10.1006/bbrc.1999.1123. PMID 10441517.
- Zhang W, Li D, Mehta JL (January 2004). "Role of AIF in human coronary artery endothelial cell apoptosis". American Journal of Physiology. Heart and Circulatory Physiology. 286 (1): H354-8. doi:10.1152/ajpheart.00579.2003. PMID 14684364.
- 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. S2CID 8541615.
- Varecha M, Amrichová J, Zimmermann M, Ulman V, Lukásová E, Kozubek M (July 2007). "Bioinformatic and image analyses of the cellular localization of the apoptotic proteins endonuclease G, AIF, and AMID during apoptosis in human cells". Apoptosis. 12 (7): 1155–71. doi:10.1007/s10495-007-0061-0. PMID 17347867. S2CID 29846503.
- 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.
External links edit
- 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.