NOD2 gene

The NOD2 gene (NOD2 stands for: Nucleotide-binding oligomerization domain-containing protein 2), also known as the NLRC2 gene or CARD15 gene, is a protein-coding gene located on chromosome 16p12-q21. The NOD2 gene codes for the protein receptor of the same name NOD2, a cytoplasmic recognition receptor (PPR). Together with other PPRs, NOD2 organizes natural and acquired immunity via the recognition of bacterial components of microbial (highly conserved) polypeptide glycans, which form the basic scaffold of the bacterial cell wall (Caruso R et al. 2014).

NOD2 belongs to the family of NOD-like receptors (NLR). These are cytoplasmic (non-membrane-bound) protein receptors that primarily recognize bacterial lipopolysaccharides and peptidoglycans. Like toll-like receptors, NOD-like receptors 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 often the starting point for 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:

The NOD domain (nucleotide binding oligomerization domain - NOD) is located centrally, C-terminally there are leucine-rich sequences (leucine-rich repeats - LRR). The effector domains CARD, pyrin or BIR are bound N-terminally. PAMPs (also known as 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 when the receptors are activated.

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

In principle, the NLRs can be divided into 2 main groups with regard 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 mainly recognizes the bacterial muramyl dipeptide, a protein of the bacterial wall that is essential for bacteria. The receptor's recognition signal leads to activation of the NF-kappaB signaling pathway via RICK and IKK-gamma.

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

Mutations in the NOD2 gene are responsible for the rare familial "early-onset sarcoidosis (EOS)" known as Blau syndrome, a sarcoidosis that usually manifests before the age of 5 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-driven functionality of the mucosal immune response to commensal intestinal organisms. Polymorphisms in the NOD2 gene are associated with hidradenitis suppurativa in combination with other gene variations (e.g. MEFV, LPIN2, NLRP3, NLRP12, PSMB8, MVK, IL1RN, PSTPIP1) (Vural S et al. 2019)

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

Recent findings indicate that NOD2 recognizes 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. Vural S et al. (2019) Association of pyrin mutations and autoinflammation with complex phenotype hidradenitis suppurativa: a case-control study. Br J Dermatol 180:1459-1467.
5. Wang MH et al. (2017) Crohn's Disease: Genetics Update. Gastroenterol Clin North Am 46:449-461.
6. 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.