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

[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...

[学科分类] 生理学

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