G Protein Signaling Modulator-3 Inhibits the Inflammasome Activity of NLRP3

Inflammasomes are multi-protein complexes that regulate maturation of the interleukin 1 beta-related cytokines IL-1 beta and IL-18 through activation of the cysteine proteinase caspase-1. NOD-like receptor family, pyrin domain containing 3 (NLRP3) protein is a key component of inflammasomes that assemble in response to a wide variety of endogenous and pathogen-derived danger signals. Activation of the NLRP3-inflammasome and subsequent secretion of IL-1 beta is highly regulated by at least three processes: transcriptional activation of both NLRP3 and pro-IL-1 beta genes, non-transcriptional priming of NLRP3, and final activation of NLRP3. NLRP3 is predominantly expressed in cells of the hematopoietic lineage. Using a yeast two-hybrid screen, we identified the hematopoietic-restricted protein, G protein signaling modulator-3 (GPSM3), as a NLRP3-interacting protein and a negative regulator of IL-1 beta production triggered by NLRP3-dependent inflammasome activators. In monocytes, GPSM3 associates with the C-terminal leucine-rich repeat domain of NLRP3. Bone marrow-derived macrophages lacking GPSM3 expression exhibit an increase in NLRP3-dependent IL-1 beta, but not TNF-alpha, secretion. Furthermore, GPSM3-null mice have enhanced serum and peritoneal IL-1 beta production following Alum-induced peritonitis. Our findings suggest that GPSM3 acts as a direct negative regulator of NLRP3 function.