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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Alum Compounds
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Animals
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Apoptosis Regulatory Proteins
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CARD Signaling Adaptor Proteins
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Caspase 1 / metabolism
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Cell Line
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Cytoskeletal Proteins / metabolism
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GTP-Binding Proteins / chemistry
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GTP-Binding Proteins / genetics
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GTP-Binding Proteins / metabolism*
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Humans
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Inflammasomes / metabolism*
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Interferon-gamma / immunology
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Interleukin-1beta / metabolism
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Lipopolysaccharides / immunology
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Listeria monocytogenes
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Listeriosis / immunology
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Macrophages / immunology
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Macrophages / metabolism*
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Mice
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NLR Family, Pyrin Domain-Containing 3 Protein
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Protein Multimerization
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RNA Interference
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Salmonella typhimurium / immunology
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Uric Acid
Substances
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Alum Compounds
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Apoptosis Regulatory Proteins
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CARD Signaling Adaptor Proteins
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Carrier Proteins
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Cytoskeletal Proteins
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GBP5 protein, human
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Inflammasomes
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Interleukin-1beta
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Lipopolysaccharides
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NLR Family, Pyrin Domain-Containing 3 Protein
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NLRP3 protein, human
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Nlrp3 protein, mouse
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PYCARD protein, human
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Pycard protein, mouse
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Uric Acid
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aluminum sulfate
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Interferon-gamma
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Caspase 1
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GTP-Binding Proteins
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Gbp5 protein, mouse