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Innate immune recognition of bacterial ligands by NAIPs dictates inflammasome specificity

Inflammasomes are a family of cytosolic multiprotein complexes that initiate innate immune responses to pathogenic microbes by activating the CASPASE1 (CASP1) protease(1,2). Although genetic data support a critical role for inflammasomes in immune defense and inflammatory diseases(3), the molecular...

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Autores principales: Kofoed, Eric M., Vance, Russell E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3184209/
https://www.ncbi.nlm.nih.gov/pubmed/21874021
http://dx.doi.org/10.1038/nature10394
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author Kofoed, Eric M.
Vance, Russell E.
author_facet Kofoed, Eric M.
Vance, Russell E.
author_sort Kofoed, Eric M.
collection PubMed
description Inflammasomes are a family of cytosolic multiprotein complexes that initiate innate immune responses to pathogenic microbes by activating the CASPASE1 (CASP1) protease(1,2). Although genetic data support a critical role for inflammasomes in immune defense and inflammatory diseases(3), the molecular basis by which individual inflammasomes respond to specific stimuli remains poorly understood. The inflammasome that contains the NLRC4 (NLR family, CARD domain containing C4) protein was previously shown to be activated in response to two distinct bacterial proteins, flagellin(4,5) and PrgJ(6), a conserved component of pathogen-associated type III secretion systems. However, direct binding between NLRC4 and flagellin or PrgJ has never been demonstrated. A homolog of NLRC4, NAIP5 (NLR family, Apoptosis Inhibitory Protein 5), has been implicated in activation of NLRC4(7–11), but is widely assumed to play only an auxiliary role(1,2), since NAIP5 is often dispensable for NLRC4 activation(7,8). However, Naip5 is a member of a small multigene family(12), raising the possibility of redundancy and functional specialization among Naip genes. Indeed, we show here that different NAIP paralogs dictate the specificity of the NLRC4 inflammasome for distinct bacterial ligands. In particular, we found that activation of endogenous NLRC4 by bacterial PrgJ requires NAIP2, a previously uncharacterized member of the NAIP gene family, whereas NAIP5 and NAIP6 activate NLRC4 specifically in response to bacterial flagellin. We dissected the biochemical mechanism underlying the requirement for NAIP proteins by use of a reconstituted NLRC4 inflammasome system. We found that NAIP proteins control ligand-dependent oligomerization of NLRC4 and that NAIP2/NLRC4 physically associates with PrgJ but not flagellin, whereas NAIP5/NLRC4 associates with flagellin but not PrgJ. Taken together, our results identify NAIPs as immune sensor proteins and provide biochemical evidence for a simple receptor-ligand model for activation of the NAIP/NLRC4 inflammasomes.
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spelling pubmed-31842092012-03-29 Innate immune recognition of bacterial ligands by NAIPs dictates inflammasome specificity Kofoed, Eric M. Vance, Russell E. Nature Article Inflammasomes are a family of cytosolic multiprotein complexes that initiate innate immune responses to pathogenic microbes by activating the CASPASE1 (CASP1) protease(1,2). Although genetic data support a critical role for inflammasomes in immune defense and inflammatory diseases(3), the molecular basis by which individual inflammasomes respond to specific stimuli remains poorly understood. The inflammasome that contains the NLRC4 (NLR family, CARD domain containing C4) protein was previously shown to be activated in response to two distinct bacterial proteins, flagellin(4,5) and PrgJ(6), a conserved component of pathogen-associated type III secretion systems. However, direct binding between NLRC4 and flagellin or PrgJ has never been demonstrated. A homolog of NLRC4, NAIP5 (NLR family, Apoptosis Inhibitory Protein 5), has been implicated in activation of NLRC4(7–11), but is widely assumed to play only an auxiliary role(1,2), since NAIP5 is often dispensable for NLRC4 activation(7,8). However, Naip5 is a member of a small multigene family(12), raising the possibility of redundancy and functional specialization among Naip genes. Indeed, we show here that different NAIP paralogs dictate the specificity of the NLRC4 inflammasome for distinct bacterial ligands. In particular, we found that activation of endogenous NLRC4 by bacterial PrgJ requires NAIP2, a previously uncharacterized member of the NAIP gene family, whereas NAIP5 and NAIP6 activate NLRC4 specifically in response to bacterial flagellin. We dissected the biochemical mechanism underlying the requirement for NAIP proteins by use of a reconstituted NLRC4 inflammasome system. We found that NAIP proteins control ligand-dependent oligomerization of NLRC4 and that NAIP2/NLRC4 physically associates with PrgJ but not flagellin, whereas NAIP5/NLRC4 associates with flagellin but not PrgJ. Taken together, our results identify NAIPs as immune sensor proteins and provide biochemical evidence for a simple receptor-ligand model for activation of the NAIP/NLRC4 inflammasomes. 2011-08-28 /pmc/articles/PMC3184209/ /pubmed/21874021 http://dx.doi.org/10.1038/nature10394 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Kofoed, Eric M.
Vance, Russell E.
Innate immune recognition of bacterial ligands by NAIPs dictates inflammasome specificity
title Innate immune recognition of bacterial ligands by NAIPs dictates inflammasome specificity
title_full Innate immune recognition of bacterial ligands by NAIPs dictates inflammasome specificity
title_fullStr Innate immune recognition of bacterial ligands by NAIPs dictates inflammasome specificity
title_full_unstemmed Innate immune recognition of bacterial ligands by NAIPs dictates inflammasome specificity
title_short Innate immune recognition of bacterial ligands by NAIPs dictates inflammasome specificity
title_sort innate immune recognition of bacterial ligands by naips dictates inflammasome specificity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3184209/
https://www.ncbi.nlm.nih.gov/pubmed/21874021
http://dx.doi.org/10.1038/nature10394
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