Nod2 Is a General Sensor of Peptidoglycan through Muramyl Dipeptide (MDP) Detection

Abstract

Nod2 activates the NF-B pathway following intracellular stimulation by bacterial products. Recently, mutations in Nod2 have been shown to be associated with Crohn's disease, suggesting a role for bacteria-host interactions in the etiology of this disorder. We show here that Nod2 is a general sensor of peptidoglycan through the recognition of muramyl dipeptide (MDP), the minimal bioactive peptidoglycan motif common to all bacteria. Moreover, the 3020insC frameshift mutation, the most frequent Nod2 variant associated with Crohn's disease patients, fully abrogates Nod2-dependent detection of peptidoglycan and MDP. Together, these results impact on the understanding of Crohn's disease development. Additionally, the characterization of Nod2 as the first pathogen-recognition molecule that detects MDP will help to unravel the well known biological activities of this immunomodulatory compound.

NOD2/CARD15, TLR4 and CD14 mutations in Scottish and Irish Crohn's disease patients: evidence for genetic heterogeneity within Europe?

“…The functional relevance of TLR4 mutations may be less secure following the identification of MDP as the ligand for NOD2/CARD15. 30 Although previous data from Germany have implicated the CD14 promoter variant in disease susceptibility, we could not confirm the T-159C mutation as a susceptibility gene for CD in our population. It is of some interest that this SNP is associated with earlier age of onset, as this variant maps to the IBD5 region, which in an early study was only of genome-wide significance in families with early-onset disease.…”

“…The Irish CD group comprised 113 patients (77 females and 36 males) with a median age at diagnosis of 27.5 years (IQR [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36]. This corresponded to 38 patients diagnosed before the age of 40 years (A1) and 21 diagnosed after the age of 40 years (A2).…”

“…Functional studies have shown that NOD2/ CARD15 is a general sensor of peptidoglycan that is mediated through the recognition of muramyl dipeptide (MDP). 30 Although it remains uncertain as to how/ whether the NOD2/CARD15 protein interacts with other protein families involved in the innate immune response, genes encoding these regulatory proteins bear investigation as potential susceptibility genes. The TLR family is involved in the recognition of pathogen-associated molecular patterns by the immune system.…”

Transcriptional and inflammasome‐mediated pathways for the induction of IL‐1β production by Mycobacterium tuberculosis

“…a receptor of bacterial peptidoglycans [35] and only recently we demonstrated its role in the recognition of mycobacteria [36,37]. It has also been recently shown that common polymorphisms of NOD2 are strongly associated with TB in African-American patients [38].…”

Detailed assessment of NOD2/CARD15 exonic variation in inflammatory bowel disease in Scotland: implications for disease pathogenesis

“…28 Muramyl dipeptide, the minimal essential structure of bacterial peptidoglycan carried on bacterial cell walls, is specifically recognised by the LRR domain. 29 Binding of bacteria modifies the inflammatory response within the cell by an effect on nuclear factor-kB activity. 30 Expression of NOD2/CARD15 is found within intestinal epithelial cells with highest concentrations of NOD2/ CARD15 mRNA found in Paneth cells.…”