TheUbiquitinSystem,Autophagy,andRegulatedProteinDegradationAlexanderVarshavskyDivisionofBiologyandBiologicalEngineering,CaliforniaInstituteofTechnology,Pasadena,California91125;email:avarsh@caltech.eduAnnu.Rev.Biochem.2017.86:123–28TheAnnualReviewofBiochemistryisonlineatbiochem.annualreviews.orghttps://doi.org/10.1146/annurev-biochem-061516-044859Copyrightc⃝2017byAnnualReviews.AllrightsreservedKeywordsubiquitin,proteasome,polyubiquitin,proteindegradation,autophagy,N-endrule,ubiquitin-likeAbstractThisbriefdisquisitionabouttheearlyhistoryofstudiesonregulatedproteindegradationintroducesseveraldetailedreviewsabouttheubiquitinsystemandautophagy.123Clickheretoviewthisarticle'sonlinefeatures:•DownloadfiguresasPPTslides•Navigatelinkedreferences•Downloadcitations•Explorerelatedarticles•SearchkeywordsANNUALREVIEWSFurtherAnnu.Rev.Biochem.2017.86:123-128.Downloadedfromwww.annualreviews.orgAccessprovidedbyUniversityofCalifornia-SanDiegoon06/28/17.Forpersonaluseonly.Proteolysis(proteindegradation)ismediatedbyproteases,whichrangefromrelativelysmallmonomericproteinstolargemulti-subunitproteasestermedproteasomes.Foraverylongtimeanddespitesomeevidencetothecontrary,mostintracellularproteinswerebelievedtobelong-lived.Thisassumptionsurvivednearlyintactuntilthe1980s,whentwocomplementarysetsofdiscoveriesweremade,largelybytwogroupsofresearchers,thelaboratoryofA.HershkoattheTechnion(Haifa,Israel)andmylaboratory,thenatMIT(Cambridge,UnitedStates).Throughtheelegantuseofbiochemicalfractionationandenzymology,Hershkoandcoworkersdiscoveredin1978–1980thatsomeproteinsaddedtoamammaliancellextractbecamecovalentlyconjugatedtoasmall(76-residue)proteintermedubiquitinandthatubiquitylatedproteinsweredestroyedbyanATP-dependentproteaseinthecellextract(1,2).Theproteasewascharacterizedbyseverallaboratoriesmuchlater,inthe1990s,andisnowtermedthe26Sproteasome(3–6).In1981–1983,Hershkoandcoworkersidentifiedasetofenzymes,termedE1,E2,andE3,thatmediatetheconjugationofubiquitinandtherebyconfershorthalf-liv...
