selfinhibition of synthesis and antigen presentation by epstein 和爱泼斯坦自我抑制抗原呈递的合成.ppt

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1、Self-InhibitionofSynthesisandAntigenPresentationbyEpstein-BarrVirus-EncodedEBNA1:AnExplanationY.Yin,B.Manoury,R.FahraeusFirst:ALittleAboutMHC-1MajorHistocompatibilityComplex-1presentsviralpeptidestoCD8+cytotoxicTcells(CTLinthispaper).InteractswithCD8a,TcellReceptor(TCR)onTCellALittleAbou

2、tMHC-1:MHC-1foundonallcellsinalltissuesIfitcanbeinfected,itwillproduceMHC-1.SometissuespresentmoreimmunesystemcellsSomepresentlesshepatocytesSomealmostnoneerythrocytes:nonucleus=noviralreplicationinefficienttohaveMHC-1ALittleAboutMHC-1:StructureTwopolypeptidechainsachain:large,threedom

3、ainsSpansmembranea1anda2formwallsofcleftonsurfaceofmoleculeb2Microglobulin:small,immunoglobulin-likedomainMHC-1bindsshortpeptidesof8-10a.a.inlengthEndsofpeptidebindtogrooveCanalsobindpeptidesatanchorresiduespolymorphismsALittleAboutMHC-1:PeptideProcessingInER:MHC-1astabilizedbycalnexinb

4、2mthenbinds;a:b2mbindstochaperones,TAPviatapasin.Incytosol:ProteasomedigestscytosolicproteinsTAPchanneldeliverssmallpeptidestoMHCMHCexportedtooutermembraneAndNowthePaper:Question:howdoesGArworktopreventEBNA1antigenpresentationbyMHC-1?Basics:Whatisknown:GArofEBNA1inhibitsantigenpresentati

5、ononMHC-1OriginalHypothesis:GArwasfirstthoughttoinhibitproteasomedegradationnopeptidetobepresentedonMHC-1NewHypothesis:Coupledwiththeabove,GAralsoinhibitsmRNAtranslationofEBNA1lessproteintobedigestedbyproteasome,presentedbyMHC-1OldHypothesis:OriginalHypothesis:GArwasfirstthoughttoinhib

6、itproteasomedegradationnopeptidetobepresentedonMHC-1Observed:CellsfailtopresentantigenonMHC-1whenGArispresentontranscriptFusionofGArtootherproteinpreventsantigenpresentationoffusedproteinGArincreaseshalf-lifeofEBNA1byinhibitingdegradationbyproteasomeOldHypothesis:OriginalHypothesis:GArw

7、asfirstthoughttoinhibitproteasomedegradationnopeptidetobepresentedonMHC-1Problems:Noobservedhighersteady-stateleveloffullEBNA1vs.EBDGAReversehasbeenfoundNowaytopreventDefectiveRibosomalProducts(DRiPs)fromproteasomedigestion,MHC-1presentation.HowDoesGArInhibitTranslation