Nod2

NOD2 ("Nucleotide-binding oligomerization domain-containing protein 2"), also known as NLRC2 is a protein receptor that in humans is encoded by the NOD2 gene (chromosome 16p12-q21). NOD2 is a cytoplasmic recognition receptor (PPR). NOD2, together with other PPRs, oganizes natural and acquired immunity via recognition of bacterial components of microbial (highly conserved) polypeptide glycans, which are the basic scaffold of the bacterial cell wall (Caruso R et al. 2014).

NOD2 belongs to the NOD-like receptor (NLR) family. These are cytoplasmic (non-membrane) protein receptors that recognize mainly bacterial lipopolysaccharides and peptidoglycans. Like Toll-like receptors, NOD-like recept ors belong to the large group of pathogen recognition receptors (PPR). These are similar in structure to the PPRs of plants (in plants these proteins are used to defend against predators). They are not infrequently the starting point of allergic reactions in humans). NOD-like receptors represent an important component of innate immunity.

Biochemically, NOD-like receptors (NLR) are characterized by a three-part domain structure:

Centrally located is the eponymous NOD domain (nucleotide binding oligomerization domain - NOD), C-terminally located are leucine-rich repeats (LRR). N-terminally, the effector domains CARD, pyrin or BIR are bound. PAMPs (also MAMPs-microbial/pathogen associated molecular pattern) are recognized and bound via the leucine-rich docking sites. The N-terminal domain defines which signaling pathways are induced downstream upon receptor activation.

NOD-like receptors activate an inflammatory response via the expression of antimicrobial peptides (AMPs). Furthermore, NOD-like receptors induce processes of apoptosis via mechanisms that have not yet been clearly elucidated.

In principle, NLRs can be divided into 2 main groups with respect to their functionality: the NLRC group with the two main representatives NOD1 and NOD2, and the inflammasome-activating NLRs with their main representatives, the NLRPs.

NOD2 is mainly produced by monocytes, dendritic cells and intestinal epithelial cells. NOD2 recognizes the bacterial Muramyl dipeptide, a protein of the bacterial wall that is essential for bacteria. The recognition signal of the receptor leads via RICK and IKK-gamma to an activation of the NF-KappaB signalling pathway.

Polymorphisms of the NOD1 and NOD2 genes are associated with an increased risk of developing gastric cancer. The increased risk of carcinoma is probably due to increased colonization by Helicobacter pylori, as a result of the disturbed immune system. This observation also underlines the importance of intact NOD receptors in the defence against bacterial infections (Zhou YJ et al. 2015)

Mutations in the NOD2 gene are responsible for the rare familial "early-onset sarcoidosis (EOS)", the so-called blue syndrome, a sarcoidosis usually manifesting before the age of 5 years with arthritis, uveitis and exanthema. (Caso F et al. 2015).

Furthermore, polymorphisms in the NOD2 gene are associated with a significantly increased risk of developing Crohn's disease. It is assumed that NOD2 polymorphisms lead to a deficient immune response to intestinal bacteria. This demonstrates the important, NOD2-directed functionality of the mucosal immune response to commensal, intestinal organisms.

Furthermore, the presence of mutations in the NOD2 gene is associated with a high risk of developing an "intestinal graft-versus-host reaction" after stem cell transplantation.

Recent findings suggest that NOD2 recognises viral as well as bacterial patterns and activates the viral immune response.

1. Caso F et al. (2015) Autoinflammatory granulomatous diseases: from Blau syndrome and early-onset sarcoidosis to NOD2-mediated disease and Crohn's disease. RMD Open 1:e000097.
2. Caruso R et al. (2014) NOD1 and NOD2: signaling, host defense, and inflammatory disease. Immunity 41:898-908.
3. Strober W et al (2014) Cellular and molecular mechanisms underlying NOD2 risk-associated polymorphisms in Crohn's disease. Immunol Rev 260:249-260.

4. Wang MH et al (2017) Crohn's disease: genetics update. Gastroenterol Clin North Am 46:449-461.

5. Zhou YJ et al. (2015) Increased NOD1, but not NOD2, activity in subcutaneous adipose tissue from patients with metabolic syndrome. Obesity (Silver Spring) 23:1394-1400.