Differential Requirements for NAIP5 in Activation of the NLRC4 Inflammasome

School of Public Health, Division of Immunology & Pathogenesis, , University ofCalifornia, Berkeley, California 94720, USA.
Infection and immunity (Impact Factor: 3.73). 03/2011; 79(4):1606-14. DOI: 10.1128/IAI.01187-10
Source: PubMed


Inflammasomes are cytosolic multiprotein complexes that assemble in response to infectious or noxious stimuli and activate
the CASPASE-1 protease. The inflammasome containing the nucleotide binding domain-leucine-rich repeat (NBD-LRR) protein NLRC4
(interleukin-converting enzyme protease-activating factor [IPAF]) responds to the cytosolic presence of bacterial proteins
such as flagellin or the inner rod component of bacterial type III secretion systems (e.g., Salmonella PrgJ). In some instances, such as infection with Legionella pneumophila, the activation of the NLRC4 inflammasome requires the presence of a second NBD-LRR protein, NAIP5. NAIP5 also is required
for NLRC4 activation by the minimal C-terminal flagellin peptide, which is sufficient to activate NLRC4. However, NLRC4 activation
is not always dependent upon NAIP5. In this report, we define the molecular requirements for NAIP5 in the activation of the
NLRC4 inflammasome. We demonstrate that the N terminus of flagellin can relieve the requirement for NAIP5 during the activation
of the NLRC4 inflammasome. We also demonstrate that NLRC4 responds to the Salmonella protein PrgJ independently of NAIP5. Our results indicate that NAIP5 regulates the apparent specificity of the NLRC4 inflammasome
for distinct bacterial ligands.

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    • "Extracellular flagellin is recognized by TLR5 (16) but it can be delivered to the cell cytosol though the secretion systems present in virulent bacteria strains, such as the S. typhimurium type III secretion system (T3SS SPI-1) and L. pneumophila type IV (T4SS). In the cell cytosol, flagellin induces the formation of the NAIP5/NLRC4 inflammasome, leading to the subsequent activation of caspase-1 (17, 18, 23). Notably, the activation NAIP5/NLRC4 inflammasomes by cytosolic flagellin occurs independently of TLR5 (20), and these two receptors recognize distinct regions of flagellin (16). "
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    ABSTRACT: Neuronal apoptosis inhibitory protein (NAIP)/NOD-like receptor (NLR) containing a caspase activating and recruitment domain (CARD) 4 (NLRC4) inflammasome complexes are acti-vated in response to proteins from virulent bacteria that reach the cell cytosol. Specific NAIP proteins bind to the agonists and then physically associate with NLRC4 to form an inflammasome complex able to recruit and activate pro-caspase-1. NAIP5 and NAIP6 sense flagellin, component of flagella from motile bacteria, whereas NAIP1 and NAIP2 detect needle and rod components from bacterial type III secretion systems, respectively. Active caspase-1 mediates the maturation and secretion of the pro-inflammatory cytokines, IL-1β and IL-18, and is responsible for the induction of pyroptosis, a pro-inflammatory form of cell death. In addition to these well-known effector mechanisms, novel roles have been described for NAIP/NLRC4 inflammasomes, such as phagosomal maturation, activation of inducible nitric oxide synthase, regulation of autophagy, secretion of inflammatory media-tors, antibody production, activation of T cells, among others. These effector mechanisms mediated by NAIP/NLRC4 inflammasomes have been extensively studied in the context of resistance of infections and the potential of their agonists has been exploited in therapeutic strategies to non-infectious pathologies, such as tumor protection. Thus, this review will discuss current knowledge about the activation of NAIP/NLRC4 inflammasomes and their effector mechanisms.
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    • "Absent in melanoma 2 (AIM2) responds to the presence of cytosolic double-stranded DNA (Hornung et al., 2009; Roberts et al., 2009). In mice, ICE-protease activating factor (IPAF)/NLR family, CARD domain containing 4 (NLRC4) mediates inflammasome activation in response to three distinct stimuli—flagellin, the conserved inner rod component of the bacterial T3SS (PrgJ), and T3SS needle proteins (Franchi et al., 2006; Miao et al., 2006, 2010b; Lightfield et al., 2011; Yang et al., 2013). Biochemical studies have shown that the NLRs neuronal apoptosis inhibitory protein 5 (NAIP5) and NAIP6 coimmunoprecipitate with flagellin, while NAIP2 interacts specifically with PrgJ and NAIP1 interacts with the needle proteins (Kofoed and Vance, 2011; Zhao et al., 2011; Yang et al., 2013). "
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    ABSTRACT: Cell death can be critical for host defense against intracellular pathogens because it eliminates a crucial replicative niche, and pro-inflammatory cell death can alert neighboring cells to the presence of pathogenic organisms and enhance downstream immune responses. Pyroptosis is a pro-inflammatory form of cell death triggered by the inflammasome, a multi-protein complex that assembles in the cytosol to activate caspase-1. Inflammasome activation by pathogens hinges upon violation of the host cell cytosol by activities such as the use of pore-forming toxins, the use of specialized secretion systems, or the cytosolic presence of the pathogen itself. Recently, a non-canonical inflammasome has been described that activates caspase-11 and also leads to pro-inflammatory cell death. Caspase-11 is activated rapidly and robustly in response to violation of the cytosol by bacterial pathogens as well. In this mini-review, we describe the canonical and non-canonical inflammasome pathways that are critical for host defense against a model intracellular bacterial pathogen that accesses the host cytosol-Legionella pneumophila.
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    • "NLRC4 directly binds to cytosolic flagellin, an event that promotes its oligomerization through the nucleotide-binding domain (NBD) and winged-helix domain (WHD) in the presence of adenosine diphosphate (ADP) (81). The importance of IPAF-dependent activation of caspase-1 has been highlighted in infection models in vitro using Salmonella typhimurium, S. flexneri, Legionella pneumophila, and P. aeruginosa (66, 70, 74). In such experiments, IPAF-deficient macrophages were impaired in their ability to activate caspase-1 and secrete IL-1β and IL-18. "
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    ABSTRACT: Since they were first described as cytosolic sensors of microbial molecules a decade ago, the Nod-like receptors (NLRs) have been shown to have many different and important roles in various aspects of immune and inflammatory responses, ranging from antimicrobial mechanisms to control of adaptive responses. In this review, we focus on the interplay between NLRs and autophagy, an evolutionarily conserved mechanism that is crucial for homeostasis and has recently been shown to be involved in the protective response against infections. Furthermore, the association between mutations of NLRs as well as proteins that form the autophagic machinery and inflammatory diseases such as Crohn's disease highlight the importance of these proteins and their interactions in the regulation of inflammation.
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