Pattern Recognition Receptor - Types - Cytoplasmic PRRs - NOD-like Receptors (NLR)

NOD-like Receptors (NLR)

For more details, see NOD-like receptor.

The NOD-like receptors (NLRs) are cytoplasmic proteins that regulate inflammatory and apoptotic responses. Approximately 20 of these proteins have been found in the mammalian genome and include two major subfamilies called NODs and NALPs, the MHC Class II transactivator (CIITA), IPAF, BIRC1, and other molecules. This family of proteins is greatly expanded in plants, and constitutes a core component of plant immune systems. Some of these proteins recognize endogenous or microbial molecules or stress responses and form oligomers that, in animals, activate inflammatory caspases (e.g. caspase 1) causing cleavage and activation of important inflammatory cytokines such as IL-1, and/or activate the NF-κB signaling pathway to induce production of inflammatory molecules. The NLR family is known under several different names, including the CATERPILLER (or CLR) or NOD-LRR family.

NODs

The ligands are currently known for NOD1 and NOD2. NOD1 recognizes a molecule called meso-DAP, which is a peptidoglycan constituent only of Gram negative bacteria. NOD2 proteins recognize intracellular MDP (muramyl dipeptide), which is a peptidoglycan constituent of both Gram positive and Gram negative bacteria. NODs transduce signals in the pathway of NF-κB and MAP kinases via the serine-threonine kinase called RIP2. NOD proteins are so named because they contain a nucleotide-binding oligomerization domain which binds nucleoside triphosphate. NODs signal via N-terminal CARD domains to activate downstream gene induction events, and interact with microbial molecules by means of a C-terminal leucine-rich repeat (LRR) region.

NALPs

Like NODs, these proteins contain C-terminal LRRs, which appear to act as a regulatory domain and may be involved in the recognition of microbial pathogens. Also like NODs, these proteins also contain a nucleotide binding site (NBS) for nucleoside triphosphates. Interaction with other proteins (e.g. the adaptor molecule ASC) is mediated via N-terminal pyrin (PYD) domain. There are 14 members of this subfamily in humans (called NALP1 to NALP14). Mutations in NALP3 are responsible for the autoinflammatory diseases familial cold autoinflammatory syndrome, Muckle-Wells syndrome and neonatal onset multisystem inflammatory disease. Activators of NALP3 include muramyl dipeptide, bacterial DNA, 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 IPAF and NAIP5/Birc1e have also been shown to activate caspase-1 in response to Salmonella and Legionella.