Inositol polyphosphate multikinase promotes Toll-like receptor-induced inflammation by stabilizing TRAF6

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dc.contributor.authorKim, Eunhako
dc.contributor.authorBeon, Jiyoonko
dc.contributor.authorLee, Seulgiko
dc.contributor.authorPark, Seung Juko
dc.contributor.authorAhn, Hyoungjoonko
dc.contributor.authorKim, Min Gyuko
dc.contributor.authorPark, Jeong Eunko
dc.contributor.authorKim, Wooseobko
dc.contributor.authorYuk, Jae-Minko
dc.contributor.authorKang, Suk-Joko
dc.contributor.authorLee, Seung-Hyoko
dc.contributor.authorJo, Eun-Kyeongko
dc.contributor.authorSeong, Rho Hyunko
dc.contributor.authorKim, Seyunko
dc.date.accessioned2017-07-04T02:25:56Z-
dc.date.available2017-07-04T02:25:56Z-
dc.date.created2017-05-16-
dc.date.created2017-05-16-
dc.date.issued2017-04-
dc.identifier.citationSCIENCE ADVANCES, v.3, no.4, pp.e1602296 - e1602296-
dc.identifier.issn2375-2548-
dc.identifier.urihttp://hdl.handle.net/10203/224566-
dc.description.abstractToll-like receptor (TLR) signaling is tightly controlled to protect hosts from microorganisms while simultaneously preventing uncontrolled immune responses. Tumor necrosis factor receptor-associated factor 6 (TRAF6) is a critical mediator of TLR signaling, but the precise mechanism of how TRAF6 protein stability is strictly controlled still remains obscure. We show that myeloid-specific deletion of inositol polyphosphate multikinase (IPMK), which has both inositol polyphosphate kinase activities and noncatalytic signaling functions, protects mice against polymicrobial sepsis and lipopolysaccharide-induced systemic inflammation. IPMK depletion in macrophages results in decreased levels of TRAF6 protein, thereby dampening TLR-induced signaling and proinflammatory cytokine production. Mechanistically, the regulatory role of IPMK is independent of its catalytic function, instead reflecting its direct binding to TRAF6. This interaction stabilizes TRAF6 by blocking its K48-linked ubiquitination and subsequent degradation by the proteasome. Thus, these findings identify IPMK as a key determinant of TRAF6 stability and elucidate the physiological function of IPMK in TLR-induced innate immunity.-
dc.languageEnglish-
dc.publisherAMER ASSOC ADVANCEMENT SCIENCE-
dc.subjectNF-KAPPA-B-
dc.subjectMEDIATED IMMUNE-RESPONSES-
dc.subjectINNATE IMMUNITY-
dc.subjectNEGATIVE REGULATION-
dc.subjectADAPTER TRAF6-
dc.subjectKINASE TAK1-
dc.subjectACTIVATION-
dc.subjectTRANSCRIPTION-
dc.subjectDEGRADATION-
dc.subjectCOACTIVATOR-
dc.titleInositol polyphosphate multikinase promotes Toll-like receptor-induced inflammation by stabilizing TRAF6-
dc.typeArticle-
dc.identifier.wosid000401954800026-
dc.identifier.scopusid2-s2.0-85034847044-
dc.type.rimsART-
dc.citation.volume3-
dc.citation.issue4-
dc.citation.beginningpagee1602296-
dc.citation.endingpagee1602296-
dc.citation.publicationnameSCIENCE ADVANCES-
dc.identifier.doi10.1126/sciadv.1602296-
dc.contributor.localauthorKang, Suk-Jo-
dc.contributor.localauthorLee, Seung-Hyo-
dc.contributor.localauthorKim, Seyun-
dc.contributor.nonIdAuthorKim, Wooseob-
dc.contributor.nonIdAuthorYuk, Jae-Min-
dc.contributor.nonIdAuthorJo, Eun-Kyeong-
dc.contributor.nonIdAuthorSeong, Rho Hyun-
dc.description.isOpenAccessY-
dc.type.journalArticleArticle-
dc.subject.keywordPlusNF-KAPPA-B-
dc.subject.keywordPlusMEDIATED IMMUNE-RESPONSES-
dc.subject.keywordPlusINNATE IMMUNITY-
dc.subject.keywordPlusNEGATIVE REGULATION-
dc.subject.keywordPlusADAPTER TRAF6-
dc.subject.keywordPlusKINASE TAK1-
dc.subject.keywordPlusACTIVATION-
dc.subject.keywordPlusTRANSCRIPTION-
dc.subject.keywordPlusDEGRADATION-
dc.subject.keywordPlusCOACTIVATOR-
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