G protein signaling modulator-3 inhibits the inflammasome activity of NLRP3

Patrick M. Giguère, Bryan J. Gall, Ejiofor A.D. Ezekwe, Geneviève Laroche, Brian K. Buckley, Chahnaz Kebaier, Justin E. Wilson, Jenny P. Ting, David P. Siderovski, Joseph A. Duncan

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

Inflammasomes are multi-protein complexes that regulate maturation of the interleukin 1β-related cytokines IL-1β 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-1β is highly regulated by at least three processes: transcriptional activation of both NLRP3 and pro-IL-1β genes, non-transcriptional priming of NLRP3, and final activation of NLRP3. NLRP3is 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-1β 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-1β, but not TNF-α, secretion. Furthermore, GPSM3-null mice have enhanced serum and peritoneal IL-1β production following Alum-induced peritonitis. Our findings suggest that GPSM3 acts as a direct negative regulator of NLRP3 function.

Original languageEnglish
Pages (from-to)33245-33257
Number of pages13
JournalJournal of Biological Chemistry
Volume289
Issue number48
DOIs
StatePublished - 28 Nov 2014

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