title: The NLRC4 inflammasome receptors for bacterial flagellin and type III secretion apparatus.
abstract: Inflammasomes are large cytoplasmic complexes that sense microbial infections/danger molecules and induce caspase-1 activation-dependent cytokine production and macrophage inflammatory death. The inflammasome assembled by the NOD-like receptor (NLR) protein NLRC4 responds to bacterial flagellin and a conserved type III secretion system (TTSS) rod component. How the NLRC4 inflammasome detects the two bacterial products and the molecular mechanism of NLRC4 inflammasome activation are not understood. Here we show that NAIP5, a BIR-domain NLR protein required for Legionella pneumophila replication in mouse macrophages, is a universal component of the flagellin-NLRC4 pathway. NAIP5 directly and specifically interacted with flagellin, which determined the inflammasome-stimulation activities of different bacterial flagellins. NAIP5 engagement by flagellin promoted a physical NAIP5-NLRC4 association, rendering full reconstitution of a flagellin-responsive NLRC4 inflammasome in non-macrophage cells. The related NAIP2 functioned analogously to NAIP5, serving as a specific inflammasome receptor for TTSS rod proteins such as Salmonella PrgJ and Burkholderia BsaK. Genetic analysis of Chromobacterium violaceum infection revealed that the TTSS needle protein CprI can stimulate NLRC4 inflammasome activation in human macrophages. Similarly, CprI is specifically recognized by human NAIP, the sole NAIP family member in human. The finding that NAIP proteins are inflammasome receptors for bacterial flagellin and TTSS apparatus components further predicts that the remaining NAIP family members may recognize other unidentified microbial products to activate NLRC4 inflammasome-mediated innate immunity.
authors.affiliation: Graduate Program in Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhao
authors.forename: Jieling
authors.initials: J
authors.lastname: Yang
authors.forename: Jianjin
authors.initials: J
authors.lastname: Shi
authors.forename: Yi-Nan
authors.initials: YN
authors.lastname: Gong
authors.forename: Qiuhe
authors.initials: Q
authors.lastname: Lu
authors.forename: Hao
authors.initials: H
authors.lastname: Xu
authors.forename: Liping
authors.initials: L
authors.lastname: Liu
authors.forename: Feng
authors.initials: F
authors.lastname: Shao
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000276:immunology* / Q000378:metabolism*; D058947:Bacterial Secretion Systems / Q000276:immunology*; D053468:CARD Signaling Adaptor Proteins / Q000276:immunology* / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000276:immunology* / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism; D002460:Cell Line; D002861:Chromobacterium / Q000235:genetics / Q000276:immunology / Q000502:physiology; D005408:Flagellin / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D058847:Inflammasomes / Q000276:immunology* / Q000378:metabolism; D016952:Legionella pneumophila / Q000276:immunology / Q000502:physiology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D051616:Neuronal Apoptosis-Inhibitory Protein / Q000276:immunology / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D058947:Bacterial Secretion Systems; D053468:CARD Signaling Adaptor Proteins; D002135:Calcium-Binding Proteins; D058847:Inflammasomes; C512299:Ipaf protein, mouse; C496800:NAIP protein, human; C435692:NLRC4 protein, human; C496802:Naip2 protein, mouse; C496806:Naip5 protein, mouse; D051616:Neuronal Apoptosis-Inhibitory Protein; D005408:Flagellin; D020170:Caspase 1