Thenucleotide-binding oligomerization domain-like receptors, orNOD-like receptors (NLRs) (also known as nucleotide-binding leucine-rich repeat receptors),[1] are intracellular sensors ofpathogen-associated molecular patterns (PAMPs) that enter the cell viaphagocytosis or pores, anddamage-associated molecular patterns (DAMPs) that are associated with cell stress. They are types ofpattern recognition receptors (PRRs),[2] and play key roles in the regulation ofinnate immune response. NLRs can cooperate withtoll-like receptors (TLRs) and regulate inflammatory andapoptotic response.
NLRs primarily recognizeGram-positive bacteria, whereas TLRs primarily recognizeGram-negative bacteria. They are found inlymphocytes,macrophages,dendritic cells and also in non-immune cells, for example inepithelium.[3] NLRs are highly conserved through evolution. Their homologs have been discovered in many different animal species (APAF1)[4][5] and also in the plant kingdom (disease-resistance R protein).[5]
NLRs contain three domains – a centralNACHT (NOD or NBD – nucleotide-binding domain) domain, which is common to all NLRs, whilemost NLRs[clarify] also have a C-terminalleucine-rich repeat (LRR) and a variable N-terminal interaction domain. The NACHT domain mediates ATP-dependent self-oligomerization and LRR senses the presence of ligand. The N-terminal domain is responsible for homotypic protein-protein interaction and it can consist ofcaspase recruitment domain (CARD),pyrin domain (PYD), acidic transactivating domain[citation needed] orbaculovirus inhibitor repeats (BIRs).[3][6]
Names as CATERPILLER, NOD, NALP, PAN, NACHT, PYPAF were used to describe the NLRs family. The nomenclature was unified by theHUGO Gene Nomenclature Committee in 2008. The family was characterized as NLRs to provide description of the families features – NLR means nucleotide-binding domain and leucine-rich repeat containing gene family.[7]
This system divides NLRs into 4 subfamilies based on the type of N-terminal domain:
There is also an additional subfamily NLRX which doesn't have significant homology to any N-terminal domain. A member of this subfamily isNLRX1.[8]
On the other hand, NLRs can be divided into 3 subfamilies with regard to their phylogenetic relationships:
NODs subfamily consists of NOD1, NOD2, NOD3, NOD4 with CARD domain, CIITA containing acidic transactivator domain and NOD5 without any N-terminal domain.[9][10]
The well-described receptors are NOD1 and NOD2. The recognition of their ligands recruits oligomerization of NACHT domain and CARD-CARD interaction with CARD-containing serine-threoninkinase RIP2 which leads to activation of RIP2.[11] RIP2 mediates the recruitment of kinase TAK1 which phosphorylates and activatesIκB kinase. The activation of IκB kinase results in the phosphorylation of inhibitor IκB which releasesNF-κB and its nuclear translocation. NF-κB then activates expression ofinflammatory cytokines.[12] Mutations in NOD2 are associated withCrohn's disease[13] orBlau syndrome.[14]
NOD1 and NOD2 recognizepeptidoglycan motifs from bacterial cell which consists ofN-acetylglucosamine andN-acetylmuramic acid. These sugar chains are cross-linked by peptide chains that can be sensed by NODs. NOD1 recognizes a molecule calledmeso-diaminopimelic acid (meso-DAP) mostly found inGram-negative bacteria (for exampleHelicobacter pylori,Pseudomonas aeruginosa). NOD2 proteins can sense intracellularmuramyl dipeptide (MDP), typical for bacteria such asStreptococcus pneumoniae orMycobacterium tuberculosis.[3][10]
NLRPs subfamily contains NLRP1-NLRP14 that are characterized by the presence of PYD domain. IPAF subfamily has two members – IPAF with CARD domain and NAIP with BIR domain.[9][10]
NLRPs and IPAF subfamilies are involved in the formation of theinflammasome. The best characterized inflammasome isNLRP3, the activation throughPAMPs orDAMPs leads to the oligomerization.[9] The pyrin domain of NLRs binds to an adaptor proteinASC (PYCARD) via PYD-PYD interaction. ASC contains PYD and CARD domain and links the NLRs to inactive form ofcaspase 1 through the CARD domain.[15] All these protein-protein interaction form a complex called the inflammasome. The aggregation of the pro-caspase-1 causes the autocleavage and formation of an active enzyme. Caspase-1 is important for the proteolytic processing of the pro-inflammatory cytokinesIL-1β andIL-18.[9][10]NLRP3 mutations are responsible for the autoinflammatory diseasefamilial cold autoinflammatory syndrome orMuckle–Wells syndrome.[16][17]
There are three well-characterized inflammasomes – NLRP1, NLRP3 and IPAF. The formation ofNLRP3 inflammasome can be activated byPAMPs such as microbial toxins (for example alpha-toxin ofStaphylococcus aureus) or whole pathogens, for instanceCandida albicans,Saccharomyces cerevisiae,Sendai virus,Influenza. NLRP3 recognize alsoDAMPs which indicate stress in the cell. The danger molecule can be extracellular ATP, extracellular glucose,monosodium urate (MSU) crystals, calcium pyrophosphate dihydrate (CPPD),alum,cholesterol or environmental irritants –silica,asbestos,UV irradiation and skin irritants. The presence of these molecules causes a production ofROS and K+ efflux. NLRP1 recognizes lethal toxin fromBacillus anthracis andmuramyl dipeptide. IPAF sensesflagellin fromSalmonella typhimurium,Pseudomonas aeruginosa,Listeria monocytogenes.[3][9][10]
