Signalling pathways and molecular interactions of NOD1 and NOD2

The nucleotide-binding oligomerization domain (NOD) proteins NOD1 and NOD2 are members of a recently described protein family, the NACHT (domain present in NAIP, CIITA, HET-E and TP1)-LRR (leucine-rich repeat) family (NLR family). Proteins in this family are structurally related cytosolic proteins with LRR domains (which bind microbial ligands) that are similar to those found in Toll-like receptors (TLRs). As such, NOD1 and NOD2 have important roles in innate immunity. NOD1 and NOD2 are expressed by epithelial cells and antigen-presenting cells. Through their LRR domain, they recognize conserved components of the bacterial cell-wall constituent peptidoglyan: NOD1 binds γ-D-glutamyl-meso-diaminopimelic acid, and NOD2 binds muramyl dipeptide. Such recognition leads to the oligomerization of NOD1 and NOD2, followed by activation of the downstream effector molecule RICK (receptor-interacting serine/threonine kinase). This, in turn, leads to activation of nuclear factor-κB and other effector pathways. The outcome of NOD2 signalling is complex. NOD2 can function as a mediator of innate immunity by itself, but it might also function as a modifier of innate immunity that results from TLR activity. So, there is evidence that NOD2 downregulates T-helper-1-cell responses (that is, interleukin-12 (IL-12) production) that are induced after peptidoglycan binds TLR2. By contrast, there is also evidence that NOD2 upregulates tumour-necrosis factor, IL-6 and CXC-chemokine ligand 8 (CXCL8; also known as IL-8) production induced by signalling through a broad range of TLRs. Whereas NOD1 is broadly expressed by intestinal epithelial cells, NOD2 is expressed mainly by Paneth cells, which are located at the base of the epithelial crypts. In these cells, NOD2 might be an important inducer of α-defensins, which are antibacterial peptides that have a role in host defence at the epithelial interface. Mutations in the LRR domain of the caspase-recruitment domain 15 gene (CARD15; which encodes NOD2) are associated with the development of Crohn's disease, whereas mutations in the NOD of NOD2 can lead to the development of Blau syndrome. On the basis of studies of mice that lack Card15 and mice with a mutated Card15 'knocked-in', three explanations for these associations are under consideration. In each case, the proposed mechanism leads to a dysregulated innate immune response to components of the microbial flora of the gut, so this highlights the normal role of NOD2 in mucosal homeostasis. NOD1 is activated by microbial components that gain entry to the cytosol of epithelial cells. Such activation leads to the production of chemokines and possibly other host-defence factors against potential gut pathogens. So, mice with defective NOD1 function are more susceptible to infection with Helicobacter pylori, and NOD1 might be a factor in human diseases that involve this organism.