ArticleTheUbiquitinLigaseCHIPIntegratesProteostasisandAgingbyRegulationofInsulinReceptorTurnoverGraphicalAbstractHighlightsdTheubiquitinligaseCHIPtriggersinsulinreceptorturnoverdInsulinreceptorlevelislinkedtoinsulinandIGF1signalingandlongevitydEngagementofCHIPinproteinqualitycontrollimitsinsulinreceptordegradationdProteotoxicstressaggravatesinsulinreceptorstability,drivesaging,andshortenslifespanAuthorsRigaTawo,WojciechPokrzywa,E´vaKevei,...,SvenjaAdrian,Jo¨rgHo¨hfeld,ThorstenHoppeCorrespondencehoehfeld@uni-bonn.de(J.H.),thorsten.hoppe@uni-koeln.de(T.H.)InBriefAubiquitinligasepromoteseitherlongevityorproteostasis,dependingonthecellularstatus.Tawoetal.,2017,Cell169,470–482April20,2017ª2017TheAuthor(s).PublishedbyElsevierInc.http://dx.doi.org/10.1016/j.cell.2017.04.003ArticleTheUbiquitinLigaseCHIPIntegratesProteostasisandAgingbyRegulationofInsulinReceptorTurnoverRigaTawo,1,4WojciechPokrzywa,2,4E´vaKevei,2,3,4MelekE.Akyuz,2VishnuBalaji,2SvenjaAdrian,1Jo¨rgHo¨hfeld,1,5,*andThorstenHoppe2,5,6,*1InstituteforCellBiology,UniversityofBonn,Ulrich-HaberlandStr.61a,53121Bonn,Germany2InstituteforGeneticsandCECADResearchCenter,UniversityofCologne,Joseph-StelzmannStr.26,50931Cologne,Germany3Presentaddress:SchoolofBiologicalSciences,UniversityofReading,Whiteknights,ReadingRG66AJ,UK4Theseauthorscontributedequally5Seniorauthor6LeadContact:thorsten.hoppe@uni-koeln.de*Correspondence:hoehfeld@uni-bonn.de(J.H.),thorsten.hoppe@uni-koeln.de(T.H.)http://dx.doi.org/10.1016/j.cell.2017.04.003SUMMARYAgingisattendedbyaprogressivedeclineinproteinhomeostasis(proteostasis),aggravatingtheriskforproteinaggregationdiseases.Tounderstandthecoordinationbetweenproteomeimbalanceandlongevity,weaddressedthemechanisticroleofthequality-controlubiquitinligaseCHIP,whichisakeyregulatorofproteostasis.WeobservedthatCHIPdeficiencyleadstoincreasedlevelsoftheinsulinre-ceptor(INSR)andreducedlifespanofwormsandflies.Themembrane-boundINSRregulatestheinsu-linandIGF1signaling(IIS)pathwayandtherebydefinesmetaboli...
