Elevated Proteasome Capacity Extends Replicative Lifespan in Saccharomyces cerevisiae 英文参考文献.docVIP

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Elevated Proteasome Capacity Extends Replicative Lifespan in Saccharomyces cerevisiae 英文参考文献.doc

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Elevated Proteasome Capacity Extends Replicative Lifespan in Saccharomyces cerevisiae 英文参考文献

ElevatedProteasomeCapacityExtendsReplicative LifespaninSaccharomycescerevisiae UndineKruegel1.,BrettRobison2,3.,ThomasDange1¤,Gu¨ntherKahlert4,JoeR.Delaney5,6 ,Soumya Kotireddy2,MitsuhiroTsuchiya3,ScottTsuchiyama3,ChristopherJ.Murakami5,JenniferSchleit5 ,George Sutphin5,6,DanielCarr5,KrisztinaTar1,GunnarDittmar4,MattKaeberlein5*,BrianK.Kennedy2,3*, MarionSchmidt1* 1Department of Biochemistry, Albert Einstein College of Medicine, New York, New York, United States of America, 2Department of Biochemistry, University of Washington,Seattle,Washington,UnitedStatesofAmerica,3BuckInstitute,Novato,California,UnitedStatesofAmerica,4MaxDelbrueckCenterforMolecularMedicine, Berlin,Germany,5DepartmentofPathology,UniversityofWashington,Seattle,Washington,UnitedStatesofAmerica,6DepartmentofMolecularandCellularBiology Program,UniversityofWashington,Seattle,Washington,UnitedStatesofAmerica Abstract Agingischaracterizedbytheaccumulationofdamagedcellularmacromoleculescausedbydecliningrepairandelimination pathways. An integral component employed by cells to counter toxic protein aggregates is the conserved ubiquitin/ proteasome system (UPS). Previous studies have described an age-dependent decline of proteasomal function and increased longevity correlates with sustained proteasome capacity in centenarians and in naked mole rats, a long-lived rodent.Proofforadirectimpactofenhancedproteasomefunctiononlongevity,however,isstilllacking.Todeterminethe importanceofproteasomefunctioninyeastaging,weestablishedamethodtomodulateUPScapacitybymanipulating levelsoftheUPS–relatedtranscriptionfactorRpn4.WhilecellslackingRPN4exhibitadecreasednon-adaptableproteasome pool,lossofUBR2,anubiquitinligasethatregulatesRpn4turnover,resultsinelevatedRpn4levels,whichupregulatesUPS components.IncreasedUPScapacitysignificantlyenhancesreplicativelifespan(RLS)andresistancetoproteotoxicstress, while reduced UPS capacity has opposing consequences. Despite tight transcriptional co-regulation of the UPS and oxidative de