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Sequence determinants of specific pattern-recognition of bacterial ligands by the NAIP-NLRC4 inflammasome.

ABSTRACT: The NLR apoptosis inhibitory proteins (NAIPs) function as specific cytosolic receptors for bacterial ligands to form the NAIP-NLRC4 inflammasome for anti-bacterial defenses. In mice, NAIP5/6 and NAIP2 recognize bacteria flagellin and the rod protein of the type III secretion system (T3SS), respectively. However, molecular mechanism for specific ligand pattern-recognition by the NAIPs is largely unknown. Here, through extensive domain swapping and truncation analyses, three structural domains, the pre-BIR, BIR1, and HD1, in NAIP2 and NAIP5 are identified, that are important for specific recognition of their respective ligand(s). The three domains are sufficient to confer the ligand specificity for NAIP2. Asp-18, Arg-108, and Arg-667, respectively, in the pre-BIR, BIR1 and HD1 of NAIP2 are further identified, each of which is essential for efficient binding to the rod protein. To our surprise, we find that the C-terminal leucine-rich repeat domain is dispensable for NAIP2 recognition of the T3SS rod protein, but is required for NAIP5 binding to flagellin. At the ligand side, we discover that the C-terminal 35 residues in flagellin are crucial for binding to NAIP5. Among the 35 residues, three critical residues are identified, which determine flagellin recognition by NAIP5 and subsequent inflammasome activation. The differences in the three amino-acid residues among flagellins from various pathogenic and commensal bacterial species correlate well with whether they are susceptible to NAIP5-mediated immune detection. Taken together, our studies identify critical sequence and amino-acid determinants in both NAIP receptors and the bacterial ligand flagellin that are important for the specificity of the pattern-recognition.

SUBMITTER: Yang J

PROVIDER: S-EPMC5938239 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Sequence determinants of specific pattern-recognition of bacterial ligands by the NAIP-NLRC4 inflammasome.

Yang Jingyi J Zhao Yue Y Li Peng P Yang Yi Y Zhang Ejuan E Zhong Maohua M Li Yaoming Y Zhou Dihan D Cao Yuan Y Lu Mengji M Shao Feng F Yan Huimin H

Cell discovery 20180508

The NLR apoptosis inhibitory proteins (NAIPs) function as specific cytosolic receptors for bacterial ligands to form the NAIP-NLRC4 inflammasome for anti-bacterial defenses. In mice, NAIP5/6 and NAIP2 recognize bacteria flagellin and the rod protein of the type III secretion system (T3SS), respectively. However, molecular mechanism for specific ligand pattern-recognition by the NAIPs is largely unknown. Here, through extensive domain swapping and truncation analyses, three structural domains, th ...[more]

PMID: 29760946

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Project description:Inflammasomes are a family of cytosolic multiprotein complexes that initiate innate immune responses to pathogenic microbes by activating the caspase 1 protease. Although genetic data support a critical role for inflammasomes in immune defence and inflammatory diseases, 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 4) protein was previously shown to be activated in response to two distinct bacterial proteins, flagellin and PrgJ, a conserved component of pathogen-associated type III secretion systems. However, direct binding between NLRC4 and flagellin or PrgJ has never been demonstrated. A homologue of NLRC4, NAIP5 (NLR family, apoptosis inhibitory protein 5), has been implicated in activation of NLRC4 (refs 7-11), but is widely assumed to have only an auxiliary role, as NAIP5 is often dispensable for NLRC4 activation. However, Naip5 is a member of a small multigene family, raising the possibility of redundancy and functional specialization among Naip genes. Here we show in mice that different NAIP paralogues determine 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 the NAIP2-NLRC4 complex physically associates with PrgJ but not flagellin, whereas NAIP5-NLRC4 associates with flagellin but not PrgJ. 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.

Dataset Information

Sequence determinants of specific pattern-recognition of bacterial ligands by the NAIP-NLRC4 inflammasome.

Publications

Sequence determinants of specific pattern-recognition of bacterial ligands by the NAIP-NLRC4 inflammasome.

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