Letterhttps://doi.org/10.1038/s41586-018-0433-3Alpha-kinase1isacytosolicinnateimmunereceptorforbacterialADP-heptosePingZhou1,8,YangShe1,2,3,8,NaDong4,PengLi1,HuabinHe1,AlessioBorio5,QingcuiWu1,ShanLu1,XiaojunDing6,YongCao1,YueXu1,WenqingGao1,MengqiuDong1,JingjinDing1,2,Da-ChengWang2,AllaZamyatina5&FengShao1,2,7*Immunerecognitionofpathogen-associatedmolecularpatterns(PAMPs)bypatternrecognitionreceptorsoftenactivatesproinflammatoryNF-κBsignalling1.Recentstudiesindicatethatthebacterialmetabolited-glycero-β-d-manno-heptose1,7-bisphosphate(HBP)canactivateNF-κBsignallinginhostcytosol2–4,butitisunclearwhetherHBPisagenuinePAMPandthecognatepatternrecognitionreceptorhasnotbeenidentified.HerewecombinedatransposonscreeninYersiniapseudotuberculosiswithbiochemicalanalysesandidentifiedADP-β-d-manno-heptose(ADP-Hep),whichmediatestypeIIIsecretionsystem-dependentNF-κBactivationandcytokineexpression.ADP-Hep,butnototherheptosemetabolites,couldenterhostcytosoltoactivateNF-κB.ACRISPR–Cas9screenshowedthatactivationofNF-κBbyADP-HepinvolvesanALPK1(alpha-kinase1)–TIFA(TRAF-interactingproteinwithforkhead-associateddomain)axis.ADP-HepdirectlybindstheN-terminaldomainofALPK1,stimulatingitskinasedomaintophosphorylateandactivateTIFA.ThecrystalstructureoftheN-terminaldomainofALPK1andADP-Hepincomplexrevealedtheatomicmechanismofthisligand–receptorrecognitionprocess.HBPwastransformedbyhostadenylyltransferasesintoADP-heptose7-P,whichcouldactivateALPK1toalesserextentthanADP-Hep.ADP-Hep(butnotHBP)aloneorduringbacterialinfectioninducedAlpk1-dependentinflammationinmice.OurfindingsidentifyALPK1andADP-Hepasapatternrecognitionreceptorandaneffectiveimmunomodulator,respectively.Gram-negativebacteriasuchasYersinia5,Salmonella6,Burkholderia7andenteropathogenicEscherichiacoli8induceNF-κB-mediatedcytokineexpressioninatypeIIIsecretionsystem(T3SS)-dependentmanner.Consistently,infectionof293TcellswithY.pseudotuber-culosisΔ6(lackingthesixT3SSeffectors;Δ6isomittedhereafter)robustlyactivatedNF-κB-driven...
