Syk is involved in NLRP3 inflammasome‐mediated caspase‐1 activation through adaptor ASC phosphorylation and enhanced oligomerization

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

关键词: ATP;    IL‐;    1β;    NLR;    tyrosine kinase;   

DOI  :  10.1189/jlb.3HI0814-371RR

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

NLRP3isthemostcrucialmemberoftheNLRfamily,asitdetectstheexistenceofpathogeninvasionandself‐derivedmoleculesassociatedwithcellulardamage.SeveralstudieshavereportedthatexcessiveNLRP3inflammasome‐mediatedcaspase‐1activationisakeyfactorinthedevelopmentofdiseases.RecentstudieshavereportedthatSykisinvolvedinpathogen‐inducedNLRP3inflammasomeactivation;however,thedetailedmechanismlinkingSyktoNLRP3inflammasomeremainsunclear.Inthisstudy,weshowedthatSykmediatesNLRP3stimuli‐inducedprocessingofprocaspase‐1andtheconsequentactivationofcaspase‐1.Moreover,thekinaseactivityofSykisrequiredtopotentiatecaspase‐1activationinareconstitutedNLRP3inflammasomesysteminHEK293Tcells.TheadaptorproteinASCbridgesNLRP3withtheeffectorproteincaspase‐1.Herein,wefindthatSykcanassociatedirectlywithASCandNLRP3byitskinasedomainbutinteractindirectlywithprocaspase‐1.SykcanphosphorylateASCatY146andY187residues,andthephosphorylationofbothresiduesiscriticaltoenhanceASColigomerizationandtherecruitmentofprocaspase‐1.Together,ourresultsrevealanewmolecularpathwaythroughwhichSykpromotesNLRP3inflammasomeformation,resultingfromthephosphorylationofASC.Thus,thecontrolofSykactivitymightbeeffectivetomodulateNLRP3inflammasomeactivationandtreatNLRP3‐relatedimmunediseases...

【 授权许可】

CC BY