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Science 336 (6080): 481-485

Copyright © 2012 by the American Association for the Advancement of Science

GBP5 Promotes NLRP3 Inflammasome Assembly and Immunity in Mammals

Avinash R. Shenoy,1 David A. Wellington,1,2,* Pradeep Kumar,1 Hilina Kassa,1,{dagger} Carmen J. Booth,2 Peter Cresswell,3 John D. MacMicking1,{ddagger}

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.

1 Section of Microbial Pathogenesis, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, CT 06510, USA.
2 Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06510, USA.
3 Department of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510, USA.

* Present address: Department of Comparative Medicine, Hoffmann-La Roche Inc., Nutley, NJ 07110–1199, USA.

{dagger} Present address: Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.

{ddagger} To whom correspondence should be addressed. E-mail: john.macmicking{at}yale.edu


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