Programmedcelldeathisinducedbymanydifferentfactorsandinvolvesnumeroussignalingpathways,somedependentoncaspaseproteasesandothersthatarecaspaseindependent.LikecytochromeC,AIF(apoptosis-inducingfactor)isaproteinfoundinmitochondriathatisreleasedfrommitochondriabyapoptoticstimuli.WhilecytochromeCislinkedtocaspase-dependentapoptoticsignaling,AIFreleasestimulatescaspase-independentapoptosis,movingintothenucleuswhereitbindsDNA.DNAbindingbyAIFstimulateschromatincondensation,andDNAfragmentation,perhapsthroughrecruitmentofnucleases.DNA-bindingbyAIFoccursthroughadistinctdomainoftheproteininamannerthatdoesnotrelayonspecificDNAsequences.AIFalsohasanotherdomainthatactsasanNADHoxidase,aredoxenzyme.TheNADHoxidaseactivityofAIFisseparablefromitsDNA-bindingactivityandisnotrequiredforAIFtoinduceapoptosis.Inthisrole,AIFprotectsagainstapoptosisratherthaninducingapoptosis.InmicedownregulationoftheAIFgenecreatedharlequinmicewithoxidativedamagetoneuronsandincreasedneuronalcelldeath.LossofAIFalsoincreasedsensitivitytoperoxides,suggestingthatAIFmayactasaperoxidescavenger.ThemechanismbywhichAIFprotectsagainstperoxidedamageisnotclear,butmayinvolveamoreindirectmechanismthandirectperoxidescavengingsincetheenzymedoesnotappeartohavethisactivityinvitro.ElucidatingfurthertheroleofAIFasaredoxenzymewillshedfurtherlightonitsnormalfunctioninmitochondriaaswellasitsroleinapoptosisanddisease.

Contributor:GlennCrostonPh.D.

REFERENCES:KleinJA,Longo-GuessCM,RossmannMP,SeburnKL,HurdRE,FrankelWN,BronsonRT,AckermanSL.Theharlequinmousemutationdownregulatesapoptosis-inducingfactor.Nature2002Sep26;419(6905):367-74LiptonSA,Bossy-WetzelE.DuelingactivitiesofAIFincelldeathversussurvival:DNAbindingandredoxactivity.Cell2002Oct18;111(2):147-50YeH,CandeC,StephanouNC,JiangS,GurbuxaniS,LaRochetteN,DaugasE,GarridoC,KroemerG,WuH.DNAbindingisrequiredfortheapoptogenicactionofapoptosisinducingfactor.NatStructBiol2002Sep;9(9):680-4YuSW,WangH,PoitrasMF,CoombsC,BowersWJ,FederoffHJ,PoirierGG,DawsonTM,DawsonVL.Mediationofpoly(ADP-ribose)polymerase-1-dependentcelldeathbyapoptosis-inducingfactor.Science2002Jul12;297(5579):259-63

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