Transcriptional regulation of the major HIV‐1 coreceptor, CXCR4, by the κ opioid receptor

Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society

关键词: JAK;    STAT;    IRF;   

DOI  :  10.1189/jlb.1010546

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

PreviousstudieshavedemonstratedthatKORactivationresultsindecreasedsusceptibilitytoinfectionbyHIV‐1inhumanPBMCs.Inthepresentstudies,wehavefoundthiseffectis,inpart,aresultofdown‐regulationofthemajorHIV‐1coreceptor,CXCR4.Usingacombinationofbiochemicalapproaches,ourresultsshowthatCXCR4proteinandmRNAlevelswerereducedsignificantlyfollowingKORactivation.Weevaluatedthenatureofthesignalingpathway(s),whichwereinducedbyKORactivation,usingtranscriptionfactor‐bindingarrayanalysisandcomparingextractsfromcontrolandKOR‐activatedcells.WedeterminedthattheIRFsandSTATswereinducedfollowingKORactivation,andtheseeventswereimportantfortheinhibitionofCXCR4expression.UsingchemicalinhibitorsandsiRNAconstructs,wedeterminedthatJAK2,STAT3,andIRF2werecriticalmembersofthissignaltransductionpathway.ImmediatelyfollowingKORactivation,JAK2wasphosphorylated,andthiswasrequiredforthephosphorylation/activationofSTAT3.Moreover,IRF2mRNAandproteinexpressionwerealsoup‐regulated,andfurtherstudiesusingChIPanalysisshowedthatIRF2wasinducedtobindinvivototheCXCR4promoter.ThisisthefirstreportdetailingtheinitiationofaKOR‐inducedJAK2/STAT3andIRF2signalingcascade,andthesepathwaysresultinsubstantialdown‐regulationofCXCR4expression.ThecapacityofKORtodown‐regulateCXCR4expressionmayprovideastrategyforthedevelopmentofnoveltherapeuticsfortheinhibitionofHIVreplication...

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