Characterization of a role of inositol polyphosphate multikinase in the regulation of toll-like receptor signaling

Abstract

Toll-like receptor (TLR) signaling is tightly controlled to protect hosts from microorganisms while simultaneously preventing uncontrolled immune responses. Inositol polyphosphate multikinase (IPMK) is a pleiotropic protein exhibiting both inositol phosphate kinase activity and non-catalytic functions, and is highly expressed in myeloid cells. Here, I show TLR4 stimulation by lipopolysaccharide (LPS) suppresses expression of IPMK in macrophages via miR-181c. IPMK depletion in macrophages reduced LPS-induced TLR4 signaling and inflammatory cytokine production. Consequently, myeloid-specific deletion of IPMK protected mice from experimental sepsis and endotoxemia. I show this regulatory role of IPMK is independent of its catalytic function, instead reflecting its interaction with TRAF6. This interaction stabilizes TRAF6 protein by blocking its K48-linked ubiquitination and subsequent degradation by the proteasome. Thus, my results establish IPMK as a key determinant of TRAF6 stability and elucidate the physiological function of IPMK in TLR-induced innate immunity.