REVIEWImmuneregulationbyproteinubiquitination:rolesoftheE3ligasesVHLandItchDaisukeAki1,2,QianLi1,HuiLi1,Yun-CaiLiu1,2&,JeeHoLee2&1InstituteforImmunology,Tsinghua-PekingCenterforLifeSciences,SchoolofMedicine,TsinghuaUniversity,Beijing100084,China2LaJollaInstituteforAllergyandImmunology,LaJolla,CA92037,USA&Correspondence:yuncai_liu@mail.tsinghua.edu.cn(Y.-C.Liu),jhlee@lji.org(J.H.Lee)ReceivedSeptember26,2018AcceptedOctober23,2018ABSTRACTProteinubiquitinationisanimportantmeansofpost-translationalmodificationwhichplaysanessentialroleintheregulationofvariousaspectsofleukocytedevel-opmentandfunction.ThespecificityofubiquitintaggingtoaproteinsubstrateisdeterminedbyE3ubiquitinligasesviadefinedE3-substrateinteractions.Inthisreview,wewillfocusontwoE3ligases,VHLandItch,todiscussthelatestprogressinunderstandingtheirrolesinthedifferentiationandfunctionofCD4+Thelpercellsubsets,thestabilityofregulatoryTcells,effectorfunctionofCD8+Tcells,aswellasthedevelopmentandmaturationofinnatelymphoidcells.ThebiologicalimplicationsoftheseE3ubiquitinligaseswillbehigh-lightedinthecontextofnormalanddysregulatedimmuneresponsesincludingthecontrolofhomeosta-sis,inflammation,auto-immuneresponsesandanti-tu-morimmunity.Furtherelucidationoftheubiquitinsysteminimmunecellswillhelpinthedesignofnewtherapeuticinterventionsforhumanimmunologicaldiseasesandcancer.KEYWORDSubiquitin,E3ligase,VHL,HIF,Itch,WWP2,Cbl-b,inflammation,autoimmunityINTRODUCTIONOurimmunesystemistightlyregulatedtoprotectagainstinvadingpathogens,andatthesametimetopreventfromself-destruction.Theimmuneresponsesaredependentonnumerouscellularsignalingpathwaysandtheircross-inter-actionsinimmunecells.Toachievetheselectivityanddiversityofeachpathway,post-translationalmodificationplaysanimportantroleinregulatingthefunctionofkeyproteinsduringsignaltransductioncascades.Thetaggingofasmall76aminoacidpolypeptidetoaprotein,knownasproteinubiquitination,isanessentialpost-translationalmodification.Proteinubiquitinationiscarriedoutviaasequentialenzymaticcas...
