Sensing Bacterial Infections by NAIP Receptors in NLRC4 Inflammasome Activation
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Protein Cell 2012, 3(2): 98–105 DOI 10.1007/s13238-012-2028-3 Protein & Cell REVIEW Sensing bacterial infections by NAIP receptors in NLRC4 inflammasome activation Yi-Nan Gong1, Feng Shao2 1 National Institute of Biological Sciences, Beijing 102206, China 2 Howard Hughes Medical Institute, National Institute of Biological Sciences, Beijing 102206, China Correspondence: [email protected] Received February 7, 2012 Accepted February 8, 2012 ABSTRACT microbial infection. To discriminate “microbial foreigners” from “self,” the innate immune system has evolved an array The inflammasome is an emerging new pathway in in- of germline-encoded pattern recognition receptors (PRRs), nate immune defense against microbial infection or end- which exhibits a broad specificity to a wide spectrum of ogenous danger signals. The inflammasome stimulates pathogen-associated molecular patterns (PAMPs) (Takeuchi activation of inflammatory caspases, mainly caspase-1. and Akira, 2010). Engagement of PAMPs by the cognate Caspase-1 activation is responsible for processing and PRRs mounts an inflammatory response, exemplified by secretion of IL-1β and IL-18 as well as for inducing expression and secretion of a plethora of inflammatory cyto- macrophage pyroptotic death. Assembly of the large kines, which functions to restrict microbial infection and pro- cytoplasmic inflammasome complex is thought to be mote subsequent adaptive immune response. The mem- mediated by members of NOD-like receptor (NLR) family. brane-bound Toll-like receptors (TLRs) are established to While functions of most of the NLR proteins remain to be directly recognize specific microbial products and thereby defined, several NLR proteins including NLRC4 have stimulate the proinflammatory NF-κB and interferon signaling, been shown to assemble distinct inflammasome com- leading to transcriptional induction of many cytokines. The plexes. These inflammasome pathways, particularly the cytosolic NOD-like receptors (NLRs) (Chen et al., 2009) are NLRC4 inflammasome, play a critical role in sensing and another family of PRRs that are also thought to function to restricting diverse types of bacterial infections. Here we sense microbial products, serving as an intracellular innate review recent advances in defining the exact bacterial immune surveillance mechanism. NLR proteins generally ligands and the ligand-binding receptors involved in contain an N-terminal caspase recruitment domain (CARD) NLRC4 inflammasome activation. Implications of the or a pyrin domain, a central nucleotide-binding and oli- discovery of the NAIP family of inflammasome receptors gomerization domain (NOD) and a C-terminal leucine-rich for bacterial flagellin and type III secretion apparatus on repeat (LRR) domain. This structural organization is similar to future inflammasome and bacterial infection studies are Apaf-1 in apoptosis as well as plant disease resistance (R) gene product, the latter of which mediates innate immune also discussed. defense in plants. In mammals, the NLR family contains 23 members in human and 34 members in mice (Ting et al., KEYWORDS inflammasome, NOD-like receptors, 2006, Davis et al., 2011). NLRC4, caspase-1, NAIP, type III secretion system, flagellin, NLR proteins can mediate the assembly of the so-called Salmonella, Legionella, enteropathogenic E. coli, Burkhold- inflammasome complex mainly in macrophage or dendritic eria cells. The inflammasome acts as a signaling platform for inducing caspase-1 autoprocessing and activation, which INTRODUCTION OF INFLAMMASOME IN INNATE further leads to maturation and secretion of IL-1β and IL-18 IMMUNITY (Schroder and Tschopp, 2010). Caspase-1 activation often triggers a special type of macrophage inflammatory death The innate immune system in mammals defends against termed pyroptosis (Fink and Cookson, 2006; Brodsky and 98 © Higher Education Press and Springer-Verlag Berlin Heidelberg 2012 Sensing bacterial infections by NAIP receptors in NLRC4 inflammasome activation Protein & Cell Medzhitov, 2011). Both interleukin production and macro- ticated translocation apparatus characterized by a multi-ring phage pyroptosis serve as effector mechanisms in limiting base and an inner rod (Marlovits et al., 2006), located on the bacterial replication and defending against infection (Miao et bacterial membranes and periplasm, as well as a protruding al., 2010a). The CARD or PYD domains in NLR proteins needle that forms a conduit for effector secretion (Deane et signal downstream caspase-1 activation through direct al., 2006). Many of the type III secretion apparatus subunits CARD–CARD interaction with caspase-1 or indirectly through share sequence and structural similarity to components of the inflammasome adaptor protein ASC. Similarly to Apaf-1 in bacterial flagellar export system that translocates monomeric apoptosome, NLR protein, upon sensing of the PAMP signal flagellin out of the bacteria for flagellar assembly. Therefore, it or certain endogenous danger signal, oligomerizes to form is generally believed that two systems are evolutionarily re- the large inflammasome complex, which requires nucleotide lated (Erhardt et al., 2010). Although type III secre- binding to its NOD domain (Duncan et al., 2007; Faustin et al., tion-containing bacterial pathogens, except for Shigella flex- 2007). Four NLR proteins including NLRP3 (Anand et al., neri that is nonflagellar but does harbor a flagellin-encoding 2011), NLRP6 (Chen et al., 2011; Elinav et al., 2011), NLRC4 gene, usually come with the flagellar appendage for motility, and mouse Nalp1b (Boyden and Dietrich, 2006), together there are also flagellar bacteria that do not harbor the type III with a non-NLR protein AIM2 (Hornung and Latz, 2010), have secretion system. For example, Legionella pneumophila, the been demonstrated to function in the inflammasome pathway causative agent of Legionnaires’ pneumonia and a model and play important but distinct roles in detecting and coun- intracellular pathogen, features a type IV secretion system teracting bacterial infection. that is required for L. pneumophila replication within host NLRC4 bears an N-terminal CARD domain that activates alveolar macrophage cells (Isberg et al., 2009; Ge and Shao, caspase-1 and downstream inflammasome signaling in both 2011). ASC-dependent and -independent manners (Broz et al., 2010b). Earlier genetic studies have established that NLRC is FLAGELLIN RECOGNITION BY NAIP5(6) responsible for sensing cytosolic presence of bacterial flagel- RECEPTORS lin in macrophage cells (Franchi et al., 2006; Miao et al., 2006). Recent studies on the function and mechanism of Earlier studies showed that several Salmonella spp. are cy- NLRC4 inflammasome activation have identified components totoxic to macrophage or macrophage-like cells (Chen et al., of bacterial type III secretion apparatus as additional bacterial 1996). Salmonella infection triggers caspase-1 activation, ligands for NLRC4 inflammasome and also the NAIP-family and blocking caspase-1 activation by a caspase-1-specific NLR proteins as the corresponding inflammasome receptors, inhibitor or genetic ablation inhibits Salmonella infec- which are the focus of the present review. tion-induced macrophage death (Hersh et al., 1999), sug- gesting inflammasome activation upon macrophage sensing BACTERIAL TYPE III SECRETION SYSTEM AND of Salmonella infection. Salmonella-induced inflammasome BACTERIAL INFECTION activation entails the NLR protein NLRC4 as bone marrow macrophages derived from Nlrc4 knockout mice show no Bacterial pathogens and their eukaryotic hosts have been caspase-1 activation and can survive Salmonella infection engaged in a constant battle during evolution. Bacterial (Mariathasan et al., 2004). On the bacterial side, the gene pathogens usually harbor specialized secretion systems to encoding the monomeric flagellin, the building blocks of bac- inject virulence effector proteins into host cells to manipulate terial flagella, is responsible for NLRC4-dependent caspase-1 or disrupt various host processes, particularly the innate im- activation (Franchi et al., 2006; Miao et al., 2006; Broz et al., mune defense pathway. Many Gram-negative bacterial 2010a). Mutant S. typhimurium strain lacking flagellin is defi- pathogens, such as Yersinia spp. (plague and gastrointestinal cient in activation of caspase-1 and IL-1β secretion; cyto- disorders), Salmonella spp. (typhoid or non-typhoid fever), plasmic delivery of purified flagellin into macrophages by Shigella spp. (bacillary dysentery), food-poisoning pathogenic cationic liposome or pore-forming toxins can trigger NLRC4 Escherichia coli, Burkholderia spp. (glanders in human and inflammasome activation (Franchi et al., 2006; Miao et al., animals), Pseudomonas spp. (that can infect humans, ani- 2006; Molofsky et al., 2006). Consistent with the wide pres- mals and plants), and the rare human pathogen Chromo- ence of the flagella among bacterial species, NLRC4 in- bacterium violaceum (that potentially can cause liver ab- flammasome-mediated innate immune detection has been scesses and sepsis), all harbor a so-called type III secretion observed with many other types of bacterial pathogens in- system (Galán and Wolf-Watz, 2006; Cornelis, 2010). The cluding Pseudomonas aeruginosa (Franchi et al., 2007; Sut- type III secretion system is an essential virulence mechanism terwala et al., 2007; Galle et al., 2008; Miao et al., 2008), L. for these pathogens as it usually delivers multiple effectors pneumophila (Amer et al., 2006; Molofsky et al., 2006;