Nucleotide-binding oligomerization domain containing 2: structure, function, and diseases

Abstract

Objectives: To systematically review literature about the structure and function of nucleotide-binding oligomerization domain containing 2 (NOD2) and its disease association.

Methods: The English literature was searched using keywords "NOD2" and "disease". Relevant original and review articles were reviewed.

Results: NOD2 is an intracellular protein and shares similar molecular structure with NOD1, pyrin, and cryopyrin. There are more than 100 NOD2 gene mutations, some of which have been linked to diseases such as Crohn disease, Blau syndrome, and NOD2-associated autoinflammatory disease (NAID). The NOD2 variants located in the leucine-rich repeat (LRR) region are susceptible to Crohn disease, and the variants in the nucleotide-binding domain (NBD) and in between the NBD and LRR are associated with Blau syndrome and NAID, respectively. No disease association with the gene variants has been found in rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, psoriasis/psoriatic arthritis, adult sarcoidosis, granulomatous polyangiitis, or multiple sclerosis. The potential association of the NOD2 variants with graft-versus-host-disease remains controversial. NOD2 functions mainly through RICK or RIP2 to activate p38 mitogen-activated protein kinases and NF-κB, resulting in inflammatory response, and enhanced autophagic activity. Biologic therapy may be beneficial for NOD2-associated diseases, and new drug development may be realized based upon the signaling pathways.

Conclusions: NOD2 gene mutations are associated with several diseases, and some of the mutations are of diagnostic value in Blau disease and NAID. To understand the NOD2 function, disease association, and its pathogenesis is important given the ever increasing clinical significance of NOD2.

Keywords: Autoinflamamtory disease; CARD; CARD15; Crohn disease; DM; Disease; EGFR; FMF; GPA; GVHD; Gene mutation; IBD; IPF; LRR; MAP; MDP; MS; NACHT; NAID; NBD; ND; NF-κB; NLRC2; NOD1; NOD2; NOD2-associated autoinflammatory disease; PGN; RA; RICK; RIP2; SLE; TLR; TNFα; caspase recruitment domain; caspase recruitment domain 15; central NOD-like receptor; diabetes mellitus; epidermal growth factor receptor; familial Mediterranean fever; graft-versus-host disease; granulomatous polyangiitis; idiopathic pulmonary fibrosis; inflammatory bowel disease; leucin-rich repeat; mitogen-activated protein; multiple sclerosis; muramyl dipeptide; not significant; nuclear factor-κB; nucleotide-binding domain; nucleotide-binding oligomerization domain (NOD)-like receptor with a CARD; nucleotide-binding oligomerization domain 1; nucleotide-binding oligomerization domain 2; peptidoglycan; receptor-interacting serine/threonine-protein kinase 2; rheumatoid arthritis; rip-like interacting caspase-like apoptosis-regulatory protein kinase; systemic lupus erythematosus; toll-like receptor; tumor necrosis factor α.