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

• DOI: 10.1126/sciadv.1602296
• Publication Date: 2017-04-22T01:10:50Z
• Authors: Eunha Kim; Jiyoon Beon; Seulgi Lee; Seung Ju Park; Hyoungjoon Ahn; Min Gyu Kim; Jeong Eun Park; Wooseob Kim; Jae-Min Yuk; Suk-Jo Kang; Seung-Hyo Lee; Eun-Kyeong Jo; Rho Hyun Seong; Seyun Kim
• Keywords: Proinflammatory cytokine

Toll-like receptor (TLR) signaling is tightly controlled to protect hosts from microorganisms while simultaneously preventing uncontrolled immune responses. Tumor necrosis factor receptor-associated 6 (TRAF6) a critical mediator of TLR signaling, but the precise mechanism how TRAF6 protein stability strictly still remains obscure. We show that myeloid-specific deletion inositol polyphosphate multikinase (IPMK), which has both kinase activities and noncatalytic functions, protects mice against polymicrobial sepsis lipopolysaccharide-induced systemic inflammation. IPMK depletion in macrophages results decreased levels protein, thereby dampening TLR-induced proinflammatory cytokine production. Mechanistically, regulatory role independent its catalytic function, instead reflecting direct binding TRAF6. This interaction stabilizes by blocking K48-linked ubiquitination subsequent degradation proteasome. Thus, these findings identify as key determinant elucidate physiological function innate immunity.