The NAIP/NLRC4 inflammasomes

Abstract

Inflammasomes comprise a family of cytosolic multi-protein complexes that sense infection, or other threats, and initiate inflammation via the recruitment and activation of the Caspase-1 protease. Although the precise molecular mechanism by which most inflammasomes are activated remains a subject of considerable debate, the NAIP/NLRC4 subfamily of inflammasomes is increasingly well understood. A crystal structure of NLRC4 was recently reported, and a domain in NAIPs that recognizes bacterial ligands was identified. In addition, gain-of-function mutations in NLRC4 have been shown to cause an auto-inflammatory syndrome in humans. Lastly, the NAIP/NLRC4 inflammasome has been shown to provide a novel form of cell intrinsic defense against Salmonella infection, involving expulsion of infected cells from the intestinal epithelium.

Figure 1. Specific detection of bacterial ligands by NAIPs

The needle or rod components of bacterial type III secretion systems (T3SS) are detected in the host cell cytosol by mouse NAIP1 or mouse NAIP2, respectively. Flagellin, the main structural protein comprising the flagellum, is detected by mouse NAIP5 or NAIP6. Human NAIP (hNAIP) detects the T3SS needle only and does not detect flagellin. Once NAIPs are activated in the presence of their cognate ligands, they co-assemble with NLRC4 to form an inflammasome that recruits and activates Caspase-1 (CASP1). The precise mechanism by which the needle and rod proteins access the host cell cytosol remains to be determined and may not involve direct secretion via the T3SS as shown.

Figure 2. The NAIP and NLRC4 Proteins

A. Domain structures of mouse NAIPs and NLRC4. BIR, Baculovirus inhibitor-of-apoptosis repeat; NBD, nucleotide binding domain; H1, helical domain 1; WHD, winged helix domain; H2, helical domain 2; LRR, leucine rich repeat domain; CARD, caspase activation and recruitment domain. Numbers indicate the number of amino acids in the full length proteins. B. Crystal structure of mouse NLRC4 in the auto-inhibited conformation. Structural coordinates are from the protein data bank (PDB accession number 4KXF) as reported by [29]. The NLRC4 CARD domain was truncated prior to crystallization and is therefore not shown. The positions of amino acids (Valine 341, Threonine 337, and Histidine 443) mutated in the recently reported human auto-inflammatory disease [25-27] are indicated, as is the phosphorylated serine 533.