Hepatitis B virus polymerase impairs interferon-α-induced STAT activation

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1、HepatitisBVirusPolymeraseImpairsInterferon-a–InducedSTATActivationThroughInhibitionofImportin-a5andProteinKinaseC-d1,2221,2345JieliangChen,*MinWu,*XiaonanZhang,WenZhang,ZhanqingZhang,LixiangChen,JingHe,61,2,71,21,51,428YeZheng,CuncunChen,FanWang,YunwenHu,XiaohuiZhou,C

2、ongWang,YangXu,81,2,7MengjiLu,andZhenghongYuanTreatmentwithexogenousinterferon(IFN)-aisnoteffectiveinthemajorityofpatientswithchronichepatitisBvirus(HBV)infection.RecentevidencesuggeststhatHBVhasevolvedstrategiestoblockthenucleartranslocationofsignaltransducerandactiv

3、atoroftranscrip-tion(STAT)1tolimitIFN-ainducedcellularantiviralresponses.However,itremainsunclearwhetherSTAT1translocationisimpairedinchronichepatitisBpatientsandwhatmechanismsareinvolved.HerewereportthattheexpressionofHBVpolymerase(Pol)inhumanhepaticcelllinesinhibite

4、dinductionofIFN-stimulatedgenesandresultedinaweak-enedantiviralactivityofIFN-a.EctopicexpressionofPolsuppressedIFN-ainducedSTAT1serine727phosphorylationandSTAT1/2nuclearaccumulation,whereasSTAT1tyrosine701phosphorylation,andSTAT1-STAT2heterodimerformationwerenotaffect

5、ed.FurtherstudiesdemonstratedthatPolinteractedwiththecatalyticdomainofproteinkinaseC-d(PKC-d)andperturbedPKC-dphosphorylationanditsassociationwithSTAT1,whichresultedinthesuppressionofSTAT1Ser727phosphorylation.Moreover,Polwasfoundtointerferewithnucleartransportationof

6、STAT1/2bycompetitivelybindingtotheregionofimportin-a5requiredforSTAT1/2recruitment.Truncationanalysissuggestedthatthetermi-nalproteinandRNaseHdomainsofPolwereabletobindtoPKC-dandimportin-a5,respectively,andwereresponsiblefortheinhibitionofIFN-asignaling.Moreimportantl

7、y,theinhibitionofSTAT1andPKC-dphosphorylationwereconfirmedinahydrodynamic-basedHBVmousemodel,andtheblockageofIFN-ainducedSTAT1/2nucleartransloca-tionwasobservedinHBV-infectedcellsfromliverbiopsiesofchronicHBVpatients.Conclusions:TheseresultsdemonstratearoleforPolinHBV-

8、mediatedantagonizationofIFN-asignalingandprovideapossiblemolecularmechanismbywhichHBVresiststheIFNtherapyandmaintainsitspers