NOD-like receptor

The NOD-like receptors (NLRs), in short for Nucleotide Oligomerization Domain receptors, are cytoplasmic proteins that may have a variety of functions in regulation of inflammatory and apoptotic responses. NLRs are encoded by genes from a large gene family present in many different animal species; there are more than 20 NLR genes in humans. Many are thought to serve as pattern recognition receptors (PRRs) which sense microbial products in the cytoplasm of cells, although some members have different functions. As such, it plays an important role in non-specific immunity.

Nomenclature
New terminology for NOD-like receptors was adopted by the Human Genome Organization (HUGO) in 2008 to standardize the nomenclature of NLRs. The initialism NLR (for NOD-like receptor) was redefined to provide description of the families common features: "nucleotide-binding oligomerization domain, leucine rich repeat and ", then the functionally differentiating domain such as "CARD domain containing 3" for NLRC3. Past designations for NLRs include CATERPILLER (CLR), NOD, NALP, PAN and PYPAF.

Function
NOD-like receptors may recognize endogenous or microbial molecules, perhaps including molecules produced in response to stress. They may then form oligomers that activate inflammatory caspases (e.g. caspase 1), causing cleavage and activation of important inflammatory cytokines such as IL-1. NLRs may also activate the NF-κB signaling pathway to induce production of inflammatory molecules.

Family members
Approximately 20 NLR proteins have been found in the mammalian genome. NLRs may be divided largely into two major subfamilies: the NLRCs (previously called NODs) and the NLRPs (previously called NALPs). Other NLRs include the MHC Class II transactivator (CIITA) and NAIP. The C of NLRC represents a caspase recruitment domain (CARD) these proteins possess at their N-terminus, while the P of NLRP represents a pyrin domain.

NLRC
NLRC1 and NLRC2 are known as NOD1 and NOD2, respectively. NLRC1 recognizes a molecule called Meso-diaminopimelic acid (meso-DAP), a peptidoglycan constituent unique to Gram negative bacteria. NLRC2 proteins recognize intracellular MDP (muramyl dipeptide), which is a peptidoglycan constituent of both Gram positive and Gram negative bacteria. Microbial product recognition is mediated by a C-terminal leucine-rich repeat (LRR) region, while NLRCs initiate NF-κB and MAP kinase signaling cascades by interacting RIPK2, a serine-threonine kinase, via their N-terminal CARD domain. NLRC4 (IPAF) has also been shown to activate caspase-1 in response to bacteria.

NLRP
Like NLRCs, NLRPs contain C-terminal LRRs, which appear to act as regulatory domains and may be involved in the recognition of microbial pathogens, and a nucleotide binding site for nucleoside triphosphates. NLRPs were previously known as NALPs. Interaction with other proteins (e.g., the adaptor molecule ASC) is mediated via the N-terminal pyrin (PYD) domain. There are 14 members of this subfamily in humans (NLRP1 to NLRP14). NLRP3 mutations are responsible for the autoinflammatory diseases familial cold autoinflammatory syndrome, Muckle-Wells syndrome and neonatal onset multisystem inflammatory disease. Activators of NLRP3 include muramyl dipeptide, bacterial DNA (non-methylated CpG repeats), ATP, toxins, double stranded RNA, paramyxoviruses and uric acid crystals. Although these specific molecules have been shown to activate NALP3, it remains unclear whether this is due to direct binding or due to cellular stress induced by these agents.

Other NLRs
Other NLRs such as NAIP have also been shown to activate caspase-1 in response to Salmonella and Legionella.