针对NFAT信号途径的新型免疫抑制剂

ISSN100727626CN1123870PQChineseJournalofBiochemistryandMolecularBiology2008524(5):391397NFAT,,3(,212013)cyclosporinAFK2506calcineurin(CaN),T(NFAT),.,CaN,.NFAT,,,NFAT,,,.,,.T;;;R97915NewImmunosuppressantsTargetedtoNFATSignalingPENGXin,SHENWei2Hong,SHAOQi2Xiang3(DepartmentofImmunology,SchoolofMedicalTechnology,JiangsuUniversity,Zhenjiang212013,China)AbstractTheNFAT(nuclearfactorofactivatedT)familymembersoftranscriptionfactorsplaycentralrolesintheimmunesystem.TheiractivationprocesseshavebeentargetedfortheimmunosuppressivedrugslikecyclosporineAandFK2506,whichbindtotheircorrespondentintracellularreceptorscyclophilinAandFKBP12,toinhibitthephosphataseactivityofCaNandthenuclearlocalizationofNFATproteins,thuspreventimmuneresponse.Althoughtheclinicaladministrationofthesedrugsseemedtobeeffective,theseclassicimmunosuppressantsintervenecalcineurinactivityandleadtoseveresideeffects.Recently,studiesoftheNFATsignalinghaverevealedanumberofnaturalandsyntheticimmunosuppressiveagents,whichtargetedtoNFATdownstreamsignaltransductionpathways,tobemoreselectiveandlesstoxic.Thisreviewfocusesontheadvancesintheseimmunosuppressiveagentsandtheanalysisoftheircharacteristics.WewillalsopresentthedetailedstructuresofNFATandpredictsomepotentialtargetsofnoveltherapeuticsforposttransplantrejectionandautoimmunediseases.KeywordsNFAT(nuclearfactorofactivatedT);immunosuppressant;calcineurin;signaltransduction:2007209227;:2008201227(NO:30671984)3Tel:[phone];Fax:05112850389652309;E2mail:[e-mail]:September27,2007;Accepted:January27,2008SupportedbyNationalNaturalScienceFoundationofChina(No.30671984)3CorrespondingauthorTel:0511285033768,E2mail:[e-mail](nuclearfactorofactivatedT,NFAT),,(IL22IL24IL23IL210IL213IFN2GM2CSF)(CD40LCD95L)[1].,NFAT.NFATNFAT1NFAT2NFAT1NFAT4NFATT[24].T,,,NFAT.(cyclosporinA,CsA)FK2506NFAT,(immunophilin):(cyclophilinA,CyPA)12kDFK506(12kDFK5062bindingprotein,FKBP12),CaN,NFAT.2,[5].,CaN,()[1].,.NFAT,,NFAT,RNA.NFAT,.1NFAT10,NFAT1(NFATp),TIL22[6].NFAT5:NFAT1(NFATpPNFATc2)NFAT2(NFATc1)NFAT3(NFATc4)NFAT4(NFATxPNFATc3)NFAT5.,,.NFAT1NFAT2NFAT4.NC22(Fig.1A);2,1,1DNA.NFAT(NFAThomologyregion,NHR):CaN(calcineurin2bindingregion,CNBRPcalcineurin2bindingpeptid,CnBP)PxIxIT(CnBP2APCNBR1)LxVP(CnBP2BPCNBR2)(serine2richregion,SRR)2(serine2prolinerepeatmotifs,SP)(nuclearimportsignal,NLS)(nuclearexportsignal,NES).DNARELRELRel(Relhomologyregion,RHR)(Fig.1A).NFAT3,.NFAT5PTonEBP(tonicityenhancerbindingprotein).NFAT5,,T,[7].NFAT14(calcineurin,CaN).2CaNCaN.CNACNB.CNAN,CFig.1StructuraldomainsofNFATandCaN(A)NFATprototypedomain.SRR21,SRR22,SP21,SP22,SP23:phosphorylatedsites;PxIxIT,LxVP:CaNbindingsite.;NLS:nuclearlocalizationsignal;TAD:transactivationdomain;RHR:homologyregion;NRH:NFATfamilyhomologyregion;(B)CNAhasthecatalyticdomainandregulatorydomainthatcontainsaCNBbindingsite,aCaM2bindingregion,andanautoinhibitoryregion.TheCNBisabletobindCa2+throughitsfourEF2handssites29324CNB(calmodulin,CaM)C.CNB4EF2hands[8](Fig11B).CaN,NFAT.3NFATNFAT,,NFAT.,(Fig12).,NFAT,NFAT;,,C,PIP2IP3DAG.IP3,,.CaNCNB,CNA,CaMCNA,CaN,CaN[9].CaNNFATNNHR,(NLS),NFATDNA,NFAT,NFAT(AP1GATAFOXP3),.,CaN,NFAT,NFAT,.,NFAT:,,CaN,CaNNFAT,NFAT,DNA,,NFAT.NFATNFAT,,NFAT.Fig.2AmodelforsignaltransductionpathwaysofNFATInrestingcells,NFATremainsphosphorylatedinthecytoplasm.StimulibyTCR,CD28causeaincreaseinintracellularCa2+levelstoactivatestheCaNanddephosphorylateNFATtotranslocatetothenucleus.Inthenucleus,NFATbindtospecificDNAmotifswithavarietyoftranscriptionpartners(AP1,FOXP3).AssoonasCa2+signalscease,thenuclearexportofNFAToccursthroughtheNFATkinasesandtheexportinCrm1thatcompeteswithCNforNFATbinding4NFAT4.1NFATCaNNFATNCaN.PxIxIT1CaN,NFATCaN.PxIxITVIVIT[10,11],SPRIEIT(NFAT1CNBR1),NFATCaN,NFAT,CsANFAT(lymphotoxin,LT).,C11111R[12].Noguchi[13],FITC11R2VIVITJurkat2h3935:NFAT,IL2230h,60h.Kuriyama[14],FITC211R2VIVIT4h,,FITC2VIVIT.,11R2VIVIT,.2CaN(CNBR2)NFATC,LxVP[15].PxIxIT,CNBR2,NFAT,CaN.,CaNNFAT.CNBR2116Pep3NFATc3CaN[16].,CaNA113[17],CaNNFATA79(A2kinase2anchoringprotein79,AKAP79)CaN1(calcineurinbindingprotein1,Cabin21).CaNNFAT,AKAP79Cabin21,NFATCaNCaN.[18],Cabin217019001CaN,Cabin21701900CaN.PMAPionomycinNFAT.NFAT,CaN.NFAT,AKAP79CaN(calcineurinhomologousprotein,CHP)38kDFK506(38kDFK5062bindingprotein,FKBP38)(downsyndromecriticalregion,DSCR1modulatorycalcineurin2interactingprotein,MCIP1)A238L()[1923].CaN,NFAT,PxIxITTNFAT.CsAFK506,CaN2.,,VIVITCaN,CaN2NFAT.,NFAT,TNFAT.IL22NFAT,NFAT.NC13.CaN,CaN,NFAT[24]..4.2NFATDNADNA,NFAT.EMSA,DNANFAT,NFATNFAT[25].SELEX,RNADNANFATRNA.RNADNANFAT.NFAT1DNARNANFAT1NFAT2DNA;NFAT2DNARNANFAT2DNA.NFAT2RNA,NFAT2,NFAT[26].4.3NFAT1(caseinkinase1,CK1)3(glycogen2synthasekinase3,GSK3)p38(p38MAPkinase)JUNN(JUNN2terminalkinase,JNK)NFAT,.NFATNFAT,NFAT,NFAT.,(dual2specificitytyrosine2phosphorylationregulatedkinase,DYRK)NFAT[27].DYRKNFATSP23,,CK1SRR21,GSK3SP22,NFAT.4.4NFAT,2sumoylation.49324(smallubiquitin2likemodifier,SUMO),[28].NFAT1SUMO,,NFAT1.NFAT1sumoylationC,NFAT,NFAT1[29].,NFAT1N223(caspase23),FLICE(caspase28)(cellularFLICEinhibitoryprotein,longisoformtransge