Apoptosis Database

Description [+]

Synonyms: WAH-1
Species: Metazoa;Bilateria;Ecdysozoa;Nematoda; Caenorhabditis elegans
Short gene description: wah-1 encodes a putative flavin-adenine dinucleotide (FAD)-binding oxidoreductase orthologous to mammalian PDCD8 (AIF. OMIM:300169, mutated in Harlequin mice). WAH-1 is required for apoptotic DNA degratation, SCRM-1 phospholipid scramblase activity, phosphatidylserine exposure, rapid apoptosis during embryonic development, and rapid engulfment of apoptotic cells in the germline. WAH-1 is also required for normally rapid growth and large brood sizes, and has a subtle proapoptotic function revealed in ced-3 or ced-4 mutant backgrounds. WAH-1 is expressed in most, if not all, cells of embryos and larvae. WAH-1 is normally mitochondrial, but can be released into the cytosol and nucleus by EGL-1 and CED-3. residues 380-550 of WAH-1 specifically bind SCRM-1 in vitro, but not SCRM-2 through SCRM-4, and WAH-1 binding is required in liposomes for more than residual SCRM-1 activity. WAH-1 also binds and activates CPS-6, promoting apoptotic DNA degradation, and transgenic coexpression of WAH-1 with CPS-6 specifically induces ectopic CED-3-dependent apoptosis in touch receptor neurons. CPS-6 shares a genetic pathway with WAH-1, whereas CED-3, CED-4, CED-8, and NUC-1 act independently of it. WAH-1 is paralogous to C. elegans F20D6.11 and human AIFM3 (AIFL). [Source: WormBase]
Family: other
Process: apoptosis,
Pathways:
Criteria: manually curated
Curator comment:
Human ortholog(s): AIF
WIKI: WAH-1-C_elegans

References [+]

Mechanisms of AIF-mediated apoptotic DNA degradation in Caenorhabditis elegans.
Wang X, Yang C, Chai J, Shi Y, Xue D
Apoptosis-inducing factor (AIF), a mitochondrial oxidoreductase, is released into the cytoplasm to induce cell death in response to apoptotic signals. However, the mechanisms underlying this process have not been resolved. We report that inactivation of the Caenorhabditis elegans AIF homolog wah-1 by RNA interference delayed the normal progression of apoptosis and caused a defect in apoptotic DNA degradation. WAH-1 localized in C. elegans mitochondria and was released into the cytosol and nucleus by the BH3-domain protein EGL-1 in a caspase (CED-3)-dependent manner. In addition, WAH-1 associated and cooperated with the mitochondrial endonuclease CPS-6/endonuclease G (EndoG) to promote DNA degradation and apoptosis. Thus, AIF and EndoG define a single, mitochondria-initiated apoptotic DNA degradation pathway that is conserved between C. elegans and mammals. Science. 2002 Nov 22;298(5598):1587-92.

References from Human ortholog(s):

Molecular characterization of mitochondrial apoptosis-inducing factor.
Susin SA, Lorenzo HK, Zamzami N, Marzo I, Snow BE, Brothers GM, Mangion J, Jacotot E, Costantini P, Loeffler M, Larochette N, Goodlett DR, Aebersold R, Siderovski DP, Penninger JM, Kroemer G
Mitochondria play a key part in the regulation of apoptosis (cell death). Their intermembrane space contains several proteins that are liberated through the outer membrane in order to participate in the degradation phase of apoptosis. Here we report the identification and cloning of an apoptosis-inducing factor, AIF, which is sufficient to induce apoptosis of isolated nuclei. AIF is a flavoprotein of relative molecular mass 57,000 which shares homology with the bacterial oxidoreductases; it is normally confined to mitochondria but translocates to the nucleus when apoptosis is induced. Recombinant AIF causes chromatin condensation in isolated nuclei and large-scale fragmentation of DNA. It induces purified mitochondria to release the apoptogenic proteins cytochrome c and caspase-9. Microinjection of AIF into the cytoplasm of intact cells induces condensation of chromatin, dissipation of the mitochondrial transmembrane potential, and exposure of phosphatidylserine in the plasma membrane. None of these effects is prevented by the wide-ranging caspase inhibitor known as Z-VAD.fmk. Overexpression of Bcl-2, which controls the opening of mitochondrial permeability transition pores, prevents the release of AIF from the mitochondrion but does not affect its apoptogenic activity. These results indicate that AIF is a mitochondrial effector of apoptotic cell death. Nature. 1999 Feb 4;397(6718):441-6.

AIF deficiency compromises oxidative phosphorylation.
Vahsen N, Cande C, Briere JJ, Benit P, Joza N, Larochette N, Mastroberardino PG, Pequignot MO, Casares N, Lazar V, Feraud O, Debili N, Wissing S, Engelhardt S, Madeo F, Piacentini M, Penninger JM, Schagger H, Rustin P, Kroemer G
Apoptosis-inducing factor (AIF) is a mitochondrial flavoprotein that, after apoptosis induction, translocates to the nucleus where it participates in apoptotic chromatinolysis. Here, we show that human or mouse cells lacking AIF as a result of homologous recombination or small interfering RNA exhibit high lactate production and enhanced dependency on glycolytic ATP generation, due to severe reduction of respiratory chain complex I activity. Although AIF itself is not a part of complex I, AIF-deficient cells exhibit a reduced content of complex I and of its components, pointing to a role of AIF in the biogenesis and/or maintenance of this polyprotein complex. Harlequin mice with reduced AIF expression due to a retroviral insertion into the AIF gene also manifest a reduced oxidative phosphorylation (OXPHOS) in the retina and in the brain, correlating with reduced expression of complex I subunits, retinal degeneration, and neuronal defects. Altogether, these data point to a role of AIF in OXPHOS and emphasize the dual role of AIF in life and death. EMBO J. 2004 Nov 24;23(23):4679-89. Epub 2004 Nov 4.

Structure & Sequence [+]

Pfam domains: (Pfam is a large collection of protein families.)

Source	Domain Name	Start	End
PFAM A	Pyr_redox_2	241	553
PFAM A	Pyr_redox	412	508

Protein sequence [+]

Evolution [+]

Name	Relationship	Species
A_aegypti_AAEL002016-PA	orthology	Aedes
A_gambiae_AGAP008044-PA	orthology	Anopheles
NP_001007491.1	orthology	Chicken
AIFM1	orthology	Chimpanzee
C_intestinalis_ENSCINP00000012225	orthology	Ciona
IPI00712659.1	orthology	Cow
AIFM1	orthology	Dog
CG7263	orthology	Fly
AIFM1	orthology	Fugu
AIFM1	orthology	Gasterosteus
AIFM1	orthology	Gorilla
AIFM1	orthology	Horse
AIF	orthology	Human
AIFM1	orthology	Lyzard
AIFM1	orthology	Macaca
AIFM1	orthology	Medaka
AIFM1	orthology	Monodelphis
Aifm1	orthology	Mouse
AIFM1	orthology	Orangutan
AIFM1	orthology	Rabbit
Pdcd8	orthology	Rat
AIFM1	orthology	Tetraodon
pdcd8	orthology	Xenopus
T_guttata_ENSTGUP00000005365	orthology	Zebra finch
T_guttata_ENSTGUP00000016816	orthology	Zebra finch
pdcd8	orthology	Zebrafish
A_aegypti_AAEL011158-PA	paralogy	Aedes
G_gallus_ENSGALP00000039047	paralogy	Chicken
AIFM3	paralogy	Chicken
AIFM3	paralogy	Chimpanzee
C_intestinalis_ENSCINP00000015763	paralogy	Ciona
Q2KJ59_BOVIN	paralogy	Cow
CG4199	paralogy	Fly
CG10700	paralogy	Fly
T_rubripes_ENSTRUP00000030429	paralogy	Fugu
T_rubripes_ENSTRUP00000040612	paralogy	Fugu
AIFM3	paralogy	Fugu
G_aculeatus_ENSGACP00000011210	paralogy	Gasterosteus
AIFM3	paralogy	Gasterosteus
G_aculeatus_ENSGACP00000027082	paralogy	Gasterosteus
AIFM3	paralogy	Human
AIFM3	paralogy	Lyzard
A_carolinensis_ENSACAP00000014484	paralogy	Lyzard
AIFM3	paralogy	Macaca
O_latipes_ENSORLP00000003241	paralogy	Medaka
AIFM3	paralogy	Medaka
O_latipes_ENSORLP00000010037	paralogy	Medaka
Aifm3	paralogy	Mouse
AIFM3	paralogy	Orangutan
RGD1306028	paralogy	Rat
AIFM3	paralogy	Tetraodon
T_nigroviridis_ENSTNIP00000019217	paralogy	Tetraodon
T_nigroviridis_ENSTNIP00000021125	paralogy	Tetraodon
F20D6.11	paralogy	Worm
AIFM3	paralogy	Xenopus
AIFM3	paralogy	Zebra finch
LOC569177	paralogy	Zebrafish

Information from other databases [+]

Gene related links:

Gene info from Wormbase [?] Y56A3A.32
Ensembl genome browser [?] : Y56A3A.32
Expression info from Arrayexpress [?] : Y56A3A.32
Protein expression from Protein Atlas: [?] Y56A3A.32

Other links

entrezgene: 176635
refseq_dna: NM_067163
refseq_peptide: NP_499564

Click on [?] for more information.

WAH-1 (Caenorhabditis elegans)