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1、JOURNALOFVIROLOGY,Oct.2010,p.1048810500Vol.84,No.200022-538X/10/$12.00doi:10.1128/JVI.00894-10Copyright©2010,AmericanSocietyforMicrobiology.AllRightsReserved.ConvergenceofKaposisSarcoma-AssociatedHerpesvirusReactivationwithEpstein-BarrVirusLatencyandCellularGrowthMedi
2、atedbytheNotchSignalingPathwayinCoinfectedCellsSophiaSpadavecchia,OlgaGonzalez-Lopez,KylaDriscollCarroll,DianaPalmeri,andDavidM.Lukac*DepartmentofMicrobiologyandMolecularGeneticsandGraduateSchoolofBiomedicalSciences,UniversityofMedicineandDentistryofNewJersey,NewJers
3、eyMedicalSchool,Newark,NewJersey07103Received26April2010/Accepted21July2010Kaposissarcoma-associatedherpesvirus(KSHV)istheetiologicagentofprimaryeffusionlymphoma(PEL).AllPELcelllinesareinfectedwithKSHV,and70%arecoinfectedwithEpstein-Barrvirus(EBV).KSHVreactivationfrom
4、latencyrequirespromoter-specifictransactivationbytheKSHVRtaproteinthroughinteractionswithRBP-Jk(CSL),thecellularDNA-bindingcomponentoftheNotchsignaltransductionpathway.EBVtransformationofprimaryBcellsrequiresEBVnuclearantigen2(EBNA-2)tointeractwithRBP-Jktodirectthelate
5、ntviralandcellulargeneexpressionprogram.AlthoughKSHVRtaandEBVEBNA-2bothrequireRBP-Jkfortransactivation,previousstudieshavesuggestedthatRBP-Jk-dependenttransacti-vatorsdonotfunctionidentically.WehavefoundthattheEBVlatentproteinLMP-1isexpressedinlessthan5%ofKSHV/EBVPE
6、LcellsbutisinducedinanRta-dependentfashionwhenKSHVreactivates.KSHVRtatransactivatestheEBVlatencypromotersinanRBP-Jk-dependentfashionandformsaternarycomplexwithRBP-Jkonthepromoters.InBcellsthatareconditionallytransformedbyEBValone,weshowthatKSHVRtacomplementsashort-ter
7、mEBNA-2growthdeficiencyinanautocrine/paracrinemanner.ComplementationofEBNA-2deficiencybyRtadependsonRBP-JkandLMP-1,andRtatransactivationisrequiredforoptimalgrowthofKSHV/EBVPELlines.OurdatasuggestthatRtacancontributetoEBV-drivencellulargrowthbytransactivatingRBP-Jk-dep
8、endentEBVlatencygenes.However,ourdataalsosuggestthatEBNA-2andRtainducedistinctalterationsinthecellularproteomesthatcontribut
