ContentslistsavailableatScienceDirectSeminarsinCell&DevelopmentalBiologyjournalhomepage:www.elsevier.com/locate/semcdbReviewUbiquitin-dependentproteindegradationattheendoplasmicreticulumandnuclearenvelopeAdrianB.Mehrtasha,MarkHochstrasserb,a,⁎aDepartmentofMolecular,Cellular,&DevelopmentalBiology,YaleUniversity,NewHaven,06520,CT,USAbDepartmentofMolecularBiophysics&Biochemistry,YaleUniversity,NewHaven,CT,06520,USAARTICLEINFOKeywords:ProteindegradationER-associateddegradationProteasomeUbiquitinRetrotranslocationEndoplasmicreticulumABSTRACTNumerousnascentproteinsundergofoldingandmaturationwithintheluminalandmembranecompartmentsoftheendoplasmicreticulum(ER).DespitethepresenceofvariousfactorsintheERthatpromoteproteinfolding,manyproteinsfailtoproperlyfoldandassembleandaresubsequentlydegraded.RegulatoryproteinsintheERalsoundergodegradationinawaythatisresponsivetostimuliorthechangingneedsofthecell.Asinmostcellularcompartments,theubiquitin-proteasomesystem(UPS)isresponsibleforthemajorityofthedegradationattheER―inaprocesstermedER-associateddegradation(ERAD).Autophagicprocessesutilizingubiquitin-likeprotein-conjugatingsystemsalsoplayrolesinproteindegradationattheER.TheERiscontinuouswiththenuclearenvelope(NE),whichconsistsoftheouternuclearmembrane(ONM)andinnernuclearmembrane(INM).WhileERADisknownalsotooccurattheNE,onlysomeoftheERADubiquitin-ligationpathwaysfunctionattheINM.ProteindegradationmachineriesintheER/NEtargetawidevarietyofsubstratesinmultiplecellularcompartments,includingthecytoplasm,nucleoplasm,ERlumen,ERmembrane,andtheNE.Here,wereviewtheproteindegradationmachineriesoftheERandNEandtheunderlyingmechanismsdictatingrecognitionandprocessingofsubstratesbythesemachineries.1.IntroductionTheendoplasmicreticulum(ER)isamassiveintracellularorganellecomposedofacontinuousmembranesystemthatincludestheperiph-eralERandnuclearmembranes.Thenuclearenvelope(NE)isadoublelipidbilayerconsistingofanouternuclearmembrane(ONM)andinnernuclearmembrane(INM)thatencapsulatesthenucleus.WhiletheON...
