Role of Nod2 in the development of Crohn's disease

Abstract

Crohn's Disease (CD) is caused by a loss of the regulatory capacity of the immune apparatus. Nod2 is an intracellular bacterial sensor and its mutations are associated with the development of CD. Here we summarize recent and controversial findings about the role of the Nod2 mutants in the disease process.

Fig. 1

Structure of human Nod2 and the three common CD-associated mutations. CARD, caspase activation recruitment domain; NOD, nucleotide oligomerization domain; LRR, leucine rich repeats. The number coordinates refer to amino acid residues. Note that the L1007fsinsC mutation is the same as the 1007fs mutation.

Fig. 2

Model of 1007fs-mediated inhibition of IL-10 expression and its own regulation. MDP can be generated from PGN by serum lysozyme digestion extracellularly, or by hydrolases intracellularly. MDP then binds to the leucine-rich repeats (LRR) of NOD2 homodimers. MDP binding activates NOD2 and results in recruitment of the serine-threonine kinase RICK (also known as RIP2 or CARDIAK) through CARD-CARD domain interactions (Step 1). This triggers a cascade of downstream events that lead to the activation of IKK-NF-κB (Step 2) and expression of proinflammatory cytokine and induction of anti-microbial responses (Step 3). P38 MAPK is activated via TLR stimulation (Step 4). Activated p38 MAPK interacts with hnRNP-A1 in the cytosol, forming a molecular complex (Step 5). This interaction is critical for the phosphorylation of hnRNP-A1 (Step 6), which may be important for the cleavage of hnRNP-A1 into the transcriptionally active 26 kDa cleavage product. The cleaved hnRNP-A1 then moves into the nucleus, binds the IL10 TACACA element (NRE), and together with other transcription factors such as Sp1, drives IL10 transcription (Step 7), which impacts on inflammatory reactions (Step 8). The 1007fs mutant, however, has acquired a property that wt NOD2 does not have, i.e. interfering with the interaction between p38 and hnRNP-A1 (Step 9). By doing so, it reduces p38-mediated phosphorylation of hnRNP-A1, as well as hnRNP-A1 cleavage, nuclear translocation and binding to the IL10 NRE. 1007fs itself is susceptible to proteolytic degradation (our unpublished data). P, phosphorylated serine residues; CM, cell membrane; NM, nuclear membrane.