The NLRC4 inflammasome receptors for bacterial flagellin and type III secretion apparatus

• Published in: Nature (London) 2011-09, Vol.477 (7366), p.596-600
• Main Authors: Zhao, Yue, Yang, Jieling, Shi, Jianjin, Gong, Yi-Nan, Lu, Qiuhe, Xu, Hao, Liu, Liping, Shao, Feng
• Format: Article
• Language: English
• Subjects: 631/250/256/2177; 631/250/262; 631/326/41/1969/2180; 631/326/41/2536; Animals; Apoptosis Regulatory Proteins - immunology; Apoptosis Regulatory Proteins - metabolism; Bacteria; Bacterial infections; Bacterial Secretion Systems - immunology; Calcium-Binding Proteins - immunology; Calcium-Binding Proteins - metabolism; CARD Signaling Adaptor Proteins - immunology; CARD Signaling Adaptor Proteins - metabolism; Caspase 1 - metabolism; Cell Line; Chromobacterium - genetics; Chromobacterium - immunology; Chromobacterium - physiology; Flagellin - immunology; Humanities and Social Sciences; Humans; Immunity, Innate - immunology; Inflammasomes - immunology; Inflammasomes - metabolism; Legionella pneumophila - immunology; Legionella pneumophila - physiology; letter; Macrophages - immunology; Macrophages - metabolism; Macrophages - microbiology; Mice; Mice, Inbred C57BL; multidisciplinary; Neuronal Apoptosis-Inhibitory Protein - immunology; Neuronal Apoptosis-Inhibitory Protein - metabolism; Pattern recognition; Proteins; Science; Science (multidisciplinary)
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature10510

Pathogen specificity in innate immunity The inflammasomes are multiprotein complexes involved in innate immunity, and induce an immune response to pathogenic microbes by activating the caspase 1 protease. Two groups now report that the intracellular receptors known as NAIPs (NLR family, apoptosis inhibitory proteins), previously thought to have an auxiliary role in recognizing microbial proteins, are in fact central to the process. Eric Kofoed and Russell Vance, and Feng Shao and colleagues, show that different members of the NAIP family bind to different bacterial ligands, including bacterial flagellin and a conserved bacterial type III secretion system rod protein. Inflammasomes are large cytoplasmic complexes that sense microbial infections/danger molecules and induce caspase-1 activation-dependent cytokine production and macrophage inflammatory death 1 , 2 . 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 3 , 4 , 5 . 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 6 , 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.