The TLR signaling adaptor TRAM interacts with TRAF6 to mediate activation of the inflammatory response by TLR4

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

关键词: Toll‐;    like receptors;    innate immunity;    inflammation;    signal transduction;   

DOI  :  10.1189/jlb.2A0913-487R

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

TLRsactassentinelsinprofessionalimmunecellstodetectandinitiatetheinnateimmuneresponsetopathogenchallenge.TLR4isawidelyexpressedTLR,responsibleforinitiatingpotentimmuneresponsestoLPS.TRAMactstobridgeTLR4withTRIF,orchestratingtheinflammatoryresponsetopathogenchallenge.WehaveidentifiedaputativeTRAF6‐bindingmotifinTRAMthatcouldmediateanovelsignalingfunctionforTRAMinTLR4signaling.TRAMandTRAF6associationwasconfirmedbyimmunoprecipitationofendogenous,ectopicallyexpressedandrecombinantproteins,whichwasablateduponmutationofakeyGluresidueinTRAM(TRAME183A).TRAF6andTRAMwereobservedcolocalizingusingconfocalmicroscopyfollowingectopicexpressionincellsandtheabilityofTRAMandTRAME183Atoactivateluciferase‐linkedreporterassayswasdeterminedinHEK293andTRAF6‐deficientcells.Importantly,TRAM‐deficientmacrophagesreconstitutedwithTRAME183AdisplaysignificantlyreducedinflammatoryTNF‐α,IL‐6,andRANTESproteinproductioncomparedwithWTTRAM.TheseresultsdemonstrateanovelroleforTRAMinTLR4‐mediatedsignalinginregulatinginflammatoryresponsesviaitsinteractionwithTRAF6,distinctfromitsroleasabridgingadaptorbetweenTLR4andTRIF...

【 授权许可】

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