title: GBP5 promotes NLRP3 inflammasome assembly and immunity in mammals.
abstract: Inflammasomes are sensory complexes that alert the immune system to the presence of infection or tissue damage. These complexes assemble NLR (nucleotide binding and oligomerization, leucine-rich repeat) or ALR (absent in melanoma 2-like receptor) proteins to activate caspase-1 cleavage and interleukin (IL)-1β/IL-18 secretion. Here, we identified a non-NLR/ALR human protein that stimulates inflammasome assembly: guanylate binding protein 5 (GBP5). GBP5 promoted selective NLRP3 inflammasome responses to pathogenic bacteria and soluble but not crystalline inflammasome priming agents. Generation of Gbp5(-/-) mice revealed pronounced caspase-1 and IL-1β/IL-18 cleavage defects in vitro and impaired host defense and Nlrp3-dependent inflammatory responses in vivo. Thus, GBP5 serves as a unique rheostat for NLRP3 inflammasome activation and extends our understanding of the inflammasome complex beyond its core machinery.
authors.affiliation: Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Avinash R
authors.initials: AR
authors.lastname: Shenoy
authors.forename: David A
authors.initials: DA
authors.lastname: Wellington
authors.forename: Pradeep
authors.initials: P
authors.lastname: Kumar
authors.forename: Hilina
authors.initials: H
authors.lastname: Kassa
authors.forename: Carmen J
authors.initials: CJ
authors.lastname: Booth
authors.forename: Peter
authors.initials: P
authors.lastname: Cresswell
authors.forename: John D
authors.initials: JD
authors.lastname: MacMicking
mesh_terms: D000534:Alum Compounds; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D007371:Interferon-gamma / Q000276:immunology; D053583:Interleukin-1beta / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008089:Listeria monocytogenes; D008088:Listeriosis / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D055503:Protein Multimerization; D034622:RNA Interference; D012486:Salmonella typhimurium / Q000276:immunology; D014527:Uric Acid
chemical_list: D000534:Alum Compounds; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; C528873:GBP5 protein, human; D058847:Inflammasomes; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C492716:Nlrp3 protein, mouse; C402202:PYCARD protein, human; C498534:Pycard protein, mouse; D014527:Uric Acid; C041524:aluminum sulfate; D007371:Interferon-gamma; D020170:Caspase 1; D019204:GTP-Binding Proteins; C472531:Gbp5 protein, mouse