C. elegans SIRT67 Homolog SIR-2.4 Promotes DAF-16 Relocalization and Function during Stress 英文参考文献.docVIP

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C. elegans SIRT67 Homolog SIR-2.4 Promotes DAF-16 Relocalization and Function during Stress 英文参考文献.doc

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C. elegans SIRT67 Homolog SIR-2.4 Promotes DAF-16 Relocalization and Function during Stress 英文参考文献

C.elegansSIRT6/7HomologSIR-2.4PromotesDAF-16 RelocalizationandFunctionduringStress Wei-ChungChiang1.,DanielX.Tishkoff2.,BoYang2.,JoshuaWilson-Grady3,XiaokunYu4, TravisMazer4,MarkEckersdorff2¤,StevenP.Gygi3,DavidB.Lombard2,5*,Ao-LinHsu1,4,5 * 1DepartmentofMolecularandIntegrativePhysiology,UniversityofMichigan,AnnArbor,Michigan,UnitedStatesofAmerica,2DepartmentofPathology,Universityof Michigan, Ann Arbor, Michigan, United States of America, 3Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, United States of America, 4DepartmentofInternalMedicine,DivisionofGeriatricMedicine,UniversityofMichigan,AnnArbor,Michigan,UnitedStatesofAmerica,5InstituteofGerontologyand theGeriatricsCenter,UniversityofMichigan,AnnArbor,Michigan,UnitedStatesofAmerica Abstract FoxOtranscriptionfactorsandsirtuinfamilydeacetylasesregulatediversebiologicalprocesses,includingstressresponses and longevity. Here we show that the Caenorhabditis elegans sirtuin SIR-2.4—homolog of mammalian SIRT6 and SIRT7 proteins—promotesDAF-16–dependenttranscriptionandstress-inducedDAF-16nuclearlocalization.SIR-2.4isrequiredfor resistancetomultiplestressors:heatshock,oxidativeinsult,andproteotoxicity.Bycontrast,SIR-2.4islargelydispensablefor DAF-16nuclearlocalizationandfunctioninresponsetoreducedinsulin/IGF-1-likesignaling.Althoughacetylationisknown toregulatelocalizationandactivityofmammalianFoxOproteins,thismodificationhasnotbeenpreviouslydescribedon DAF-16.WefindthatDAF-16ishyperacetylatedinsir-2.4mutants.Conversely,DAF-16isacetylatedbytheacetyltransferase CBP-1, and DAF-16 is hypoacetylated and constitutively nuclear in response to cbp-1 inhibition. Surprisingly, a SIR-2.4 catalyticmutantefficientlyrescuestheDAF-16localizationdefectinsir-2.4nullanimals.AcetylationofDAF-16byCBP-1in vitroisinhibitedbyeitherwild-typeormutantSIR-2.4,suggestingthatSIR-2.4regulatesDAF-16acetylationindirectly,by preventing CBP-1-mediated acetylation under stress conditions. Taken together, our results identify SI