NOD-like Receptors and the Inflammasome Proteins

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NOD-like Receptors and the Inflammasome Proteins

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NOD-like Receptors and the Inflammasome Proteins Background

The story of nucleotide binding oligomerization domain (NOD)-like receptor (NLR) family began with work related to development. The first discovery of a protein with a NOD domain involved nematode research with the protein apoptotic protease activating factor 1 (APAF1), which plays a role in programmed cell death during development. NLRs have been shown to possess three distinct domains consisting of a C-terminal LRR domain, a central NOD domain that facilitates self-oligomerization, and an caspase-recruitment domain (CARD). The structure of NLRs was found to be similar to proteins encoded by resistance genes (R genes) in plants, which also possess a nucleotide binding domain and a LRR domain and have been shown to be involved in protective responses to pathogens in plants. This was the first indication that NLRs may have a similar protective role in mammalian immune systems. To date 23 NLR proteins have been identified in humans and many have been demonstrated to play important roles in human disease.

The two NLR family members that have been the most studied are NOD1 and NOD2. Both NOD1 and NOD2 are cytoplasmic proteins that recognize conserved components of bacteria and induce inflammation. NOD1 recognizes γ-D-glutamyl-meso-diaminopimelic acid (meso-DAP), a bacterial component specific to Gram negative and some Gram positive peptidoglycan (PGN). NOD2 has been shown to recognize muramyl dipeptide (MDP), a product of PGN degradation that is found in nearly all bacterial species. Both NOD1 and NOD2 recognize ligand through specific interactions with their LRR domains, which result in self-oligomerization through NOD domain interactions and recruitment of a serine/threonine kinase called RICK (or RIP2) by associations between the CARDs of NOD1/NOD2 and RICK. This in turn, induces the activation of TAK1 and subsequently NFκB and MAPK, similar to TLR signaling.


The NOD proteins are comprised of three distinct functional domains: an amino-terminal effector-binding domain (EBD) involved in signaling transduction and biological functions, a centrally regulatory NOD domain that mediates self-oligomerization, and carboxyl-terminal LRRs that serve as a ligand-recognition domain (LRD). Binding of the ligands, the effector domains of NOD proteins are involved in hemophilic interactions with downstream signaling partners with a CARD. The diversity of the effector domains allows NOD proteins to interact with a variety of binding partners to activate multiple signaling pathways. Upon activation, NODI and NOD2 rapidly form oligomers and then physically associate with the CARD-containing protein kinase RICK (RIPK2/RTP2/CARDIAK) through homophilic CARD-CARD interactions. RICK then interacts with IKKγ/NEMO, the regulatory subunit of the IKK complex, and further leads to the subsequent phosphorylation and degradation of IκBα by the proteasome. NFκB is then released and translocated to the nucleus, and mediates the transcription of target genes. Importantly, NOD proteins-mediated signaling pathway is independent of myeloid differentiation factor 88 (MyD88), a key adaptor molecule involved in TLR signaling pathways. NOD2 might also regulate the non-canonical NFκB pathway, which exhibits much slower kinetics and is totally dependent on the NFκB-inducing kinase (NIK). NIK associates with the p100 subunit of NFκB and induces its cleavage to active form p52, which causes the expression of a distinct subset of inflammatory genes. NIK is required for MDP-induced transcription of the chemokine CXCL13. In addition to NFκB pathway, NODI and NOD2 stimulation results in the activation of MAPK, including p38, ERK, and JNK, through the CARD-containing adaptor protein CARD9. However, when recognizing viral ssRNA genome, NOD2 could tagger the activation of IRF3 and the production of IFN-β. Administration of MDP and iE-DAP, as well as their derivatives have been shown to induce broad activity against multiple pathogens, including secretion of proinflammatory cytokines and chemokines, synthesis of nitric oxide synthase, and also the expression of adhesion molecules, all of which are critical for the innate immune response and potentiate adaptive immune response against pathogens.

The importance of NOD1 and NOD2 is further confirmed by their genetic association with human inflammatory diseases. The most common frame-shift mutations in NOD2, which result in the loss of the terminal LRR and could not detect MDP, are associated with Crohn's disease, the chronic inflammatory disease of the intestine and gastrointestinal tract. NOD2 is also implicated in the Blau syndrome, a rare long-life disorder starting in childhood and characterized by skin rashes, uveitis and recurrent arthritis, which can evolve toward camptodactyly. Genetic variants and single nucleotide polymorphisms of NOD2 that might result in inappropriate immune responses are also associated with atopic disorders. It was shown that the Crohn's disease-associated polymorphisms in NOD2 gene are also significantly associated with an increased risk for atopic diseases and hyper IgE syndrome. In addition, NOD1 polymorphisms are also associated with the development of atopic eczema, asthma, and increased serum IgE concentrations.

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