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Sci. Signal., 4 October 2011
Vol. 4, Issue 193, p. ec274
[DOI: 10.1126/scisignal.4193ec274]

EDITORS' CHOICE

Immunology Getting Choosy

John F. Foley

Science Signaling, AAAS, Washington, DC 20005, USA

Members of the NOD-like receptor (NLR) family of cytosolic proteins respond to microbial components in the cytoplasm of infected cells by forming multiprotein complexes called inflammasomes, which stimulate the processing and activation of caspase 1. This protease then processes precursor forms of the proinflammatory cytokines interleukin-1β (IL-1β) and IL-18, which induce cell death. NLRC4-containing inflammasomes are formed in response to the bacterial proteins flagellin and PrgJ, a conserved component of the type-III secretion system (TTSS); however, how NLRC4 responds to specific stimuli is unclear (see commentary by Monack). Two groups now implicate NLR family members called NAIPs (NLR family, apoptosis inhibitory proteins) in determining the ligand specificity of NLRC4 inflammasome activation. Kofoed and Vance showed that mouse macrophages lacking NAIP2 failed to activate caspase 1 or undergo cell death in response to PrgJ; however, loss of NAIP2 had no effect on cell death induced by flagellin. In contrast, NAIP5 was required for flagellin-induced caspase 1 activation but was not necessary for cell death induced by PrgJ. Experiments in a reconstituted in vitro system showed that stimulation of NLRC4 inflammasome formation by flagellin required NAIP5, and NAIP5 and flagellin were also present in the complex. In contrast, PrgJ did not induce NAIP5-NLRC4 inflammasome formation but did stimulate complex formation between NAIP2 and NLRC4. Zhao et al. also demonstrated the ability of NAIP2 and NAIP5 to activate NLRC4 inflammasome formation in mouse cells in response to distinct ligands from various bacteria. In addition, they showed that CprI (a TTSS component from Chromobacterium violaceum), but not flagellin, activated NLRC4 inflammasome formation in a human macrophage cell line and that CprI bound to NAIP, the sole human NAIP protein. Together, these data suggest that NAIP proteins bind directly to distinct microbial products and confer ligand specificity to NLRC4 inflammasomes.

E. M. Kofoed, R. E. Vance, Innate immune recognition of bacterial ligands by NAIPs determines inflammasome specificity. Nature 477, 592–595 (2011). [PubMed]

Y. Zhao, J. Yang, J. Shi, Y.-N. Gong, Q. Lu, H. Xu, L. Liu, F. Shao, The NLRC4 inflammasome receptors for bacterial flagellin and type III secretion apparatus. Nature 477, 596–600 (2011). [PubMed]

D. M. Monack, Recognition of a unique partner. Nature 477, 543–544 (2011). [Online Journal]

Citation: J. F. Foley, Getting Choosy. Sci. Signal. 4, ec274 (2011).



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