TLR9 stability and signaling are regulated by phosphorylation and cell stress

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

关键词: CpG DNA;    innate immunity;    inflammation;    autophagy;   

DOI  :  10.1189/jlb.2A0815-337R

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

Innatesensingofpathogenselicitsprotectiveimmuneresponsesthroughpatternrecognitionreceptors,includingToll‐likereceptors.AlthoughsignalingbyToll‐likereceptorsisregulatedatmultiplesteps,includinglocalization,trafficking,proteolyticcleavage,andphosphorylation,thesignificanceofpost‐translationalmodificationsandcellularstressresponseonToll‐likereceptorstabilityandsignalingisstilllargelyunknown.Inthepresentstudy,weinvestigatedtheroleofcytoplasmictyrosinemotifsinToll‐likereceptor‐9stability,proteolyticcleavage,andsignaling.WedemonstratedthattyrosinephosphorylationisessentialformouseToll‐likereceptor‐9proteinstabilityandsignaling.Uponinhibitionoftyrosinekinaseswithpiceatannol,Toll‐likereceptor‐9tyrosinephosphorylationinducedbyCpGdeoxyribonucleicacidwasinhibited,whichcorrelatedwithdecreasedsignaling.Furthermore,inhibitionofSrckinaseswith1‐tert‐Butyl‐3‐(4‐chlorophenyl)‐1H‐pyrazolo[3,4‐d]pyrimidin‐4‐aminealsoinhibitedresponsetoCpGdeoxyribonucleicacid.Toll‐likereceptor‐9proteinstabilitywasalsosensitivetoautophagy,thecellularstressresponsepathway,andinfectionbyadeoxyribonucleicacidvirus.Whereasautophagyinducedbyrapamycinorlowserumlevelscausedapreferentiallossofthematurep80proteolyticcleavageproduct,infectionwithherpessimplexvirus‐1andinductionofcellstresswithtunicamycincausedpreferentiallossoffull‐lengthToll‐likereceptor‐9,whichislocalizedtotheendoplasmicreticulum.OurdatarevealnewinformationaboutthestabilityandsignalingofToll‐likereceptor‐9andsuggestthatimmuneevasionmechanismsmayinvolvetargetedlossofinnatesensingreceptors...

【 授权许可】

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