Myeloid IPMK promotes the resolution of serum transfer-induced arthritis in mice.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by widespread joint inflammation, which leads to joint damage, disability, and mortality. Among the several types of immune cells, myeloid cells such as macrophages are critical for controlling the pathogenesis of RA. Inositol phosphates are water-soluble signaling molecules, which are synthesized by a series of enzymes including inositol phosphate kinases. Previous studies revealed actions of inositol phosphates and their metabolic enzymes in the modulation of inflammation such as Toll-like receptor-triggered innate immunity. However, the physiological roles of inositol polyphosphate (IP) metabolism in the regulation of RA remain largely uncharacterized. Therefore, our study sought to determine the role of inositol polyphosphate multikinase (IPMK), a key enzyme for IP metabolism and various cellular signaling control mechanisms, in mediating RA. Using myeloid cell-specific IPMK knockout (KO) mice, arthritis was induced via intraperitoneal K/BxN serum injection, after which disease severity was evaluated. Both wild-type and IPMK KO mice developed similar RA phenotypes; however, conditional deletion of IPMK in myeloid cells led to elevated arthritis scores during the resolution phase, suggesting that IPMK deficiency in myeloid cells impairs the resolution of inflammation. Bone marrow-derived IPMK KO macrophages exhibited no apparent defects in immunoglobulin Fc receptor (FcR) activation, osteoclast differentiation, or resolvin signaling. Taken together, our findings suggest that myeloid IPMK is a key determinant of RA resolution.

The Expanding Significance of Inositol Polyphosphate Multikinase as a Signaling Hub.

The inositol polyphosphates are a group of multifunctional signaling metabolites whose synthesis is catalyzed by a family of inositol kinases that are evolutionarily conserved from yeast to humans. Inositol polyphosphate multikinase (IPMK) was first identified as a subunit of the arginine-responsive transcription complex in budding yeast. In addition to its role in the production of inositol tetrakis- and pentakisphosphates (IP4 and IP5), IPMK also exhibits phosphatidylinositol 3-kinase (PI3-kinase) activity. Through its PI3-kinase activity, IPMK activates Akt/PKB and its downstream signaling pathways. IPMK also regulates several protein targets non-catalytically via protein-protein interactions. These non-catalytic targets include cytosolic signaling factors and transcription factors in the nucleus. In this review, we highlight the many known functions of mammalian IPMK in controlling cellular signaling networks and discuss future challenges related to clarifying the unknown roles IPMK plays in physiology and disease.

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

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.