GBP5 promotes NLRP3 inflammasome assembly and immunity in mammals

Science. 2012 Apr 27;336(6080):481-5. doi: 10.1126/science.1217141. Epub 2012 Mar 29.

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

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alum Compounds
  • Animals
  • Apoptosis Regulatory Proteins
  • CARD Signaling Adaptor Proteins
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Caspase 1 / metabolism
  • Cell Line
  • Cytoskeletal Proteins / metabolism
  • GTP-Binding Proteins / chemistry
  • GTP-Binding Proteins / genetics
  • GTP-Binding Proteins / metabolism*
  • Humans
  • Inflammasomes / metabolism*
  • Interferon-gamma / immunology
  • Interleukin-1beta / metabolism
  • Lipopolysaccharides / immunology
  • Listeria monocytogenes
  • Listeriosis / immunology
  • Macrophages / immunology
  • Macrophages / metabolism*
  • Mice
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Protein Multimerization
  • RNA Interference
  • Salmonella typhimurium / immunology
  • Uric Acid

Substances

  • Alum Compounds
  • Apoptosis Regulatory Proteins
  • CARD Signaling Adaptor Proteins
  • Carrier Proteins
  • Cytoskeletal Proteins
  • GBP5 protein, human
  • Inflammasomes
  • Interleukin-1beta
  • Lipopolysaccharides
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • Nlrp3 protein, mouse
  • PYCARD protein, human
  • Pycard protein, mouse
  • Uric Acid
  • aluminum sulfate
  • Interferon-gamma
  • Caspase 1
  • GTP-Binding Proteins
  • Gbp5 protein, mouse