title: G Protein signaling modulator-3 inhibits the inflammasome activity of NLRP3.
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. 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-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.
authors.affiliation: From the Department of Pharmacology.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Giguère
authors.affiliation: the Department of Physiology & Pharmacology, West Virginia University School of Medicine, Morgantown, West Virginia 26506.
authors.forename: Bryan J
authors.initials: BJ
authors.lastname: Gall
authors.affiliation: From the Department of Pharmacology.
authors.forename: Ejiofor A D
authors.initials: EA
authors.lastname: Ezekwe
authors.affiliation: From the Department of Pharmacology.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Laroche
authors.affiliation: From the Department of Pharmacology.
authors.forename: Brian K
authors.initials: BK
authors.lastname: Buckley
authors.affiliation: Division of Infectious Diseases, The University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599 and.
authors.forename: Chahnaz
authors.initials: C
authors.lastname: Kebaier
authors.affiliation: Department of Microbiology and Immunology.
authors.forename: Justin E
authors.initials: JE
authors.lastname: Wilson
authors.affiliation: Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center, and.
authors.forename: Jenny P
authors.initials: JP
authors.lastname: Ting
authors.affiliation: the Department of Physiology & Pharmacology, West Virginia University School of Medicine, Morgantown, West Virginia 26506 dpsiderovski@hsc.wvu.edu.
authors.forename: David P
authors.initials: DP
authors.lastname: Siderovski
authors.affiliation: From the Department of Pharmacology, Division of Infectious Diseases, The University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599 and Lineberger Comprehensive Cancer Center, and jaduncan@med.unc.edu.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Duncan
mesh_terms: D000276:Adjuvants, Immunologic / Q000009:adverse effects / Q000494:pharmacology; D000534:Alum Compounds / Q000009:adverse effects / Q000494:pharmacology; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D020730:Guanine Nucleotide Dissociation Inhibitors / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D058847:Inflammasomes / Q000235:genetics / Q000378:metabolism*; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010538:Peritonitis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D017434:Protein Structure, Tertiary
chemical_list: D000276:Adjuvants, Immunologic; D000534:Alum Compounds; D002352:Carrier Proteins; C548537:G18 protein, mouse; C487218:GPSM3 protein, human; D020730:Guanine Nucleotide Dissociation Inhibitors; C508585:IL1B protein, human; C587672:IL1B protein, mouse; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C492716:Nlrp3 protein, mouse; C041524:aluminum sulfate
keywords: Cellular Immune Response; Cytokine; G Protein; GPSM; Inflammasome; Inflammation; NLRP3; Nod-like Receptors