NAIPs: Building an innate immune barrier against bacterial pathogens

Abstract

The innate immune system of mammals encodes several families of immune detector proteins that monitor the cytosol for signs of pathogen invasion. One important but poorly understood family of cytosolic immunosurveillance proteins is the NLR (nucleotide-binding domain, leucine-rich repeat containing) proteins. Recent work has demonstrated that one subfamily of NLRs, the NAIPs (NLR family, apoptosis inhibitory proteins), are activated by specific interaction with bacterial ligands, such as flagellin. NAIP activation leads to assembly of a large multiprotein complex called the inflammasome, which initiates innate immune responses by activation of the Caspase-1 protease. NAIPs therefore appear to detect pathogen molecules via a simple and direct receptor-ligand mechanism. Interestingly, other NLR family members appear to detect pathogens indirectly, perhaps by responding to host cell "stress" caused by the pathogen. Thus, the NLR family may have evolved surprisingly diverse mechanisms for detecting pathogens.

Microinjection of Francisella tularensis and Listeria monocytogenes Reveals the Importance of Bacterial and Host Factors for Successful Replication

“…Although the finding appears paradoxical in view of the important role of MyD88 for innate immune functions, it is possible that its absence affects the cytosolic response such that the cytosol will not be permissive for LVS and Listeria, e.g., by the lack of essential metabolites. Recent studies have identified that the release of bacterial components, e.g., DNA, from the phagosome induces a specific cytosolic response (11,12,51,71,72). Although it is often assumed that the sensing of bacterial products is a prerequisite for the control of intracellularly located bacteria, it is possible that successful intracellular pathogens have developed means to exploit this host response to their advantage and that, in fact, it is a necessity for the intracytosolic bacterial replication in certain cell types.…”

“…To combat the latter group, the macrophage utilizes cytosolic sensors belonging to the Nod-like receptor (NLR) or AIM2-like receptor families (11,12). Engagement of these receptors leads to the formation of the inflammasome, a multiprotein complex composed of a sensor protein belonging to the NLR or AIM2-like families, an adaptor protein, ASC, and caspase-1 (13).…”

Emerging Concepts about NAIP/NLRC4 Inflammasomes

“…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).…”

“…Notably, the activation NAIP5/NLRC4 inflammasomes by cytosolic flagellin occurs independently of TLR5 (20), and these two receptors recognize distinct regions of flagellin (16). TLR5 senses a region present in the D1 domain of the protein, whereas the amino acid sequences recognized by NAIP5/NLRC4 inflammasomes are in the D0 domain of the molecule (18, 23, 19, 21, 22). …”

Epithelial NAIPs protect against colonic tumorigenesis

“…Also, NAIPs lack certain caspase-interaction residues within the BIR domains that would be necessary for direct inhibition of caspases, raising concern about whether NAIP can inhibit caspases in physiological settings (Scott et al, 2005;. Additionally, NAIPs mediate inflammasome-induced caspase-1 activation and induction of pyroptosis via NLRC4, which is contrary to the suggested inhibitor of apoptosis function (Kofoed and Vance, 2012). BIR domains, however, can mediate a broad range of protein-protein interactions and therefore could be implicated in diverse cellular functions in addition to inhibition of caspases.…”