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

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Toll-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.
Publisher
AMER ASSOC ADVANCEMENT SCIENCE
Issue Date
2017-04
Language
English
Article Type
Article
Keywords

NF-KAPPA-B; MEDIATED IMMUNE-RESPONSES; INNATE IMMUNITY; NEGATIVE REGULATION; ADAPTER TRAF6; KINASE TAK1; ACTIVATION; TRANSCRIPTION; DEGRADATION; COACTIVATOR

Citation

SCIENCE ADVANCES, v.3, no.4, pp.e1602296 - e1602296

ISSN
2375-2548
DOI
10.1126/sciadv.1602296
URI
http://hdl.handle.net/10203/224566
Appears in Collection
BS-Journal Papers(저널논문)MSE-Journal Papers(저널논문)
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