Nlrc4/Ipaf/CLAN/CARD12: more than a flagellin sensor

Abstract

Nlrc4 is a member of the Nod-like receptors (NLRs), a family of cytosolic receptors involved in sensing bacterial molecules. NLRs are a group of proteins containing spans of leucine-rich repeats that senses bacterial factors within the eukaryotic cytosol. The recognition of bacterial factors provokes the formation of the inflammasome complex which includes specific NLRs. The inflammasome is responsible for caspase-1 activation which leads to the cleavage and maturation of inflammatory cytokines such as IL-1beta and IL-18. Nlrc4 was considered to be a devoted flagellin sensor in eukaryotic cells. However, studies using a variety of pathogens such as Salmonella, Legionella, Shigella and Pseudomonas at high bacterial burdens revealed that Nlrc4 can mediate caspase-1 activation independent of bacterial flagellin. On the other hand, new reports showed that Nlrc4 can restrict bacterial infection independently of caspase-1. Therefore, Nlrc4 maybe involved in sensing more than one bacterial molecule and may participate in several immune complexes.

Figure 1

Schematic representation of the structure of Nlrc4. The positions of the first and last residues for the different domains of Nlrc4 are indicated.

Figure 2

The Nlrc4 inflammasome is composed of Ipaf, ASC, and caspase-1. Nlrc4 accepts ASC then caspase-1 via their CARD domains. Then, caspase-1 is activated and activates IL-1β, IL-18 and caspase-7.