NucleicAcidsResearch,20181doi:10.1093/nar/gky1007N6-methyladenosinemodificationandMETTL3modulateenterovirus71replicationHaojieHao1,2,SujuanHao1,2,HongheChen1,ZhenChen1,YanfangZhang1,JunWang1,HanzhongWang1,BoZhang1,JianmingQiu3,FeiDeng1,*andWuxiangGuan1,*1CenterforEmergingInfectiousDiseases,WuhanInstituteofVirology,ChineseAcademyofSciences,Wuhan,Hubei430071,China,2UniversityofChineseAcademyofSciences,Beijing100049,Chinaand3DepartmentofMicrobiology,MolecularGeneticsandImmunology,UniversityofKansasMedicalCenter,KansasCity,KS66160,USAReceivedJune11,2018;RevisedOctober09,2018;EditorialDecisionOctober10,2018;AcceptedOctober11,2018ABSTRACTN6-methyladenosine(m6A)constitutesoneofthemostabundantinternalRNAmodificationsandiscriticalforRNAmetabolismandfunction.IthasbeenpreviouslyreportedthatviralRNAcontainsinternalm6Amodifications;however,onlyrecentlythefunc-tionofm6AmodificationinviralRNAshasbeeneluci-datedduringinfectionsofHIV,hepatitisCvirusandZikavirus.Inthepresentstudy,wefoundthaten-terovirus71(EV71)RNAundergoesm6Amodifica-tionduringviralinfection,whichalterstheexpres-sionandlocalizationofthemethyltransferaseanddemethylaseofm6A,anditsbindingproteins.More-over,knockdownofm6AmethyltransferaseresultedindecreasedEV71replication,whereasknockdownofthedemethylasehadtheoppositeeffect.Furtherstudyshowedthatthem6Abindingproteinsalsopar-ticipateintheregulationofviralreplication.Inpar-ticular,twom6Amodificationsiteswereidentifiedintheviralgenome,ofwhichmutationsresultedinde-creasedvirusreplication,suggestingthatm6Amod-ificationplaysanimportantroleinEV71replication.Notably,wefoundthatMETTL3interactedwithvi-ralRNA-dependentRNApolymerase3Dandinducedenhancedsumoylationandubiquitinationofthe3Dpolymerasethatboostedviralreplication.Takento-gether,ourfindingsdemonstratedthatthehostm6AmodificationcomplexinteractswithviralproteinstomodulateEV71replication.INTRODUCTIONChemicalmodificationsofRNAarecriticalforRNAmetabolism,function,andlocalization.OneofthemostabundantinternalRNAmodificationsisN...
