Molecular mechanism of NOD2-mediated anti-inflammatory signalling

The Nod-like receptor protein NOD2 participates in the recognition of conserved motifs in bacterial peptidoglycan and recruits adaptor RIPK2 to induce pro-inflammatory and antimicrobial responses through the activation of NF-kB signalling. Paradoxically, several studies have revealed that loss-of-function mutations in the Card15 gene encoding NOD2 predispose people to Crohn’s disease, a chronic inflammatory condition of the gut. Our preliminary data suggest that Nod2-deficient cells display deregulated NF-kB activation and that NOD2 interacts with family member NLRP6 in a RIPK2-independent manner. Studies suggest that both of these molecules are required to mediate anti-inflammatory signalling.

We propose to mechanistically characterise the NOD2-NLRP6 interaction in response to various ligands. We will also elucidate the localisation and kinetics of NOD2-NLRP6 assembly using immunofluorescence microscopy. Finally, we will measure the impact of this interaction on pathogen survival and inflammatory activity by studying NOD2-variants associated with Crohn’s disease.

These studies will allow us to identify potential therapeutic strategies for Crohn’s disease.