The Ubiquitin-Proteasome System and Its Role in Inflammatory and Autoimmune DiseasesCellular&MolecularImmunologylview255TheUbiquitin-ProteasomeSystemandItsRoleinInflammatoryandAutoimmuneDiseasesJingsongWang,vandMichaelA.MaldonadoProteindegradationthroughtheubiquitin?-proteasomesystemisthemajorpathwayofnon?-lysosomalproteolysisofintracellularproteins.Itplaysimportantrolesinavarietyoffundamentalcellularprocessessuchasregulationofcellcycleprogression,division,developmentanddifferentiation,apoptosis,celltrafficking,andmodulationoftheimmuneandinflammatoryresponses.Thecentralelementofthissystemisthecovalentlinkageofubiquitintotargetedproteins,whichalethenrecognizedbythe26Sproteasome,anadenosinetriphosphate-dependent,multi-catalyticprotease.Damaged,oxidized,ormisfoldedproteinsaswellasregulatoryproteinsthatcontrolmanycriticalcellularfunctionsareamongthetargetsofthisdegradationprocess.Aberrationofthissystemleadstothedysregulationofcellularhomeostasisandthedevelopmentofmultiplediseases.Inthisreview,wedescribedthebasicbiochemistryandmolecularbiologyoftheubiquitin-proteasomesystem,anditscomplexroleinthedevelopmentofinflammatoryandantoimmunediseases.Inaddition.therapiesandpotentialtherapeutictargetsrelatedtotheubiquitin-proteasomesystemarediscussedaswel1.Ce/ular&MolecularImmunology.2006;3(4):255.261.ubiquitin,proteasome,proteindegradation,inflammation,autoimmunediseaseIntroductionThe2004NobelPrizeinChemistrywasawardedtoagroupofscientistsforthediscoveryofthefunctionofubiquitinn.41.Ubiquitinispartoftheubiquitin-proteasomesystem(UPS1matisresponsibleforthedegradationofmorethan80%ofnormalandabnormalintracellularproteins.Attheheartofmissystemisthe26Sproteasome.adynamicmultisubunitproteolyticcomplexwithamolecularweightof700kDthat.ineukaryotes,functionsasthekeyenzymefornon.1ysosomalproteindegradation.Proteasomaldegradationremovesdenatured,misfolded,damagedorimproperlytranslatedproteinsfromcellsandaswellasregulatingthelevelofproteinssuchascyclinsandtranscriptionfactors.Theproductsresultingfromthisenzymaticdegradationhavedifferentsequences,lengthsandbiologicalfunctions(5).ItTranslationalMedicine,WyethResearch,Collegeville,PA19426,USA;DepartmentofMedicine,UniversityofPennsylvania,Philadelphia,PA19104,USA;Correspondingto:Dr.JingsongWang,AssociateDirector,TranslationalMedicine,ClinicalResearchandDevelopment,WyethResearch,500ArcolaRoad,Collegeville,PA19426,USA.Tel:+01-4848658363,Fax:+01-4848651092,Email:jwang8wyeth.corn.ReceivedAug7,2006.AcceptedAug20,2006Copydght2006byTheChineseSocietyofImmunologyhasbeenshownthatthisisahighlyregulated,tightlycontrolled.yetcomplexsystemthatiscentraltonormalcellularhomeostasisincludingcellcycleregulation.DNArepair-sodiumchannelfunction.regulationofimmuneandinflammatoryresponsesandcellularresponsetostress(6.81.DerangementsoftheUPScanleadtomanydisorders.includingmalignancies,neurodegenerativediseasesandpossiblesystemicautoimmunity(9).BetterunderstandingoftheUPSprocessandidentificationofthecomponentsinvolvedinthedegradationofkeyregulatoryproteinshasleadtothedevelopmentofmechanism.basedtherapeuticsinvariousdiseasesf1012).Agrowingbodyofevidencesuggeststhattargetingtheproteasomalpathwayisanattractiveapproachtotreatinflammatoryandautoimmunediseases(13-15).UbiquitinandubiquitinatiOnUbiquitinisa76.residueproteinthatishighlyevolutionarilyconservedinalleukaryotes(16.17).Selectiveattachmentofubiquitintoproteinsistheinitialsignalfortargetedproteindegradation.Thelinkageofubiquitintothetargetproteinisthroughabranchedisopeptidebondbetweentheubiquitincarboxy1.terminalglycineandaninternallysineonthesubstrate.AdditionalubiquitinmoietiesaresequentiallyaddedtoeachothertoformapolyubiquitinchainthatfunctionsastherecognitionsignalforadownstreamproteasomeintheUPS.ModificationoftargetproteinsbyubiquitinoranubiquitinlikeproteinremodelsthesurfaceofVolume3Number4August2006PPI+AMPE1舀一IheUolquiiinPruImc,NyemandItsRolel1.ayAutoi1Ic1uDid0Tar口日捃匕=团-Tl州oStep2Step3pmonlccomplex(2IJSimdarlyIheproteinkinaseCandtyrosmekinasepathwaysareinvolvedinbothIhe.fleaionofbPSsubstratesndphospationElefticientlyrroteasonle20SplYm,afrflncquinatedsubsateslargclednprllteotysisarccognlZenhyproleasomesmecenlralelenlenlofIheUPSInIhepmteasomecclnplcxthecmpltcsfCP)isthbaclshaped20Scomplex120Spmteasmel(Fi2ure21Itconisisof0urslackedringseachwith7distinctsubunitackedmpofeacholhcrthatresponsibleforthproteolylicaclivit7oftheproteasonleIhclntidentiI_Itcfnngsandw,innerrinsrh【1t2rinhvefm/nownthnction,whereasthe口tingscontainmuhiplecalalytJcSlNIneukaryotes(wooltheeitcsOlltheBril1amchymotrypsiii-likefCTL),wooftheseitctrypsinlikefTUandwoilcaspase-likeEdIIalIkn.wnsyntheticandnatullpmlesonicinhihittrsacln11lhcCTLll(22JbtlmcNUr4Auu21)060专屯Cellular&M0JImmunuklgy19SRegulato