Inflammatory bowel disease: NOD2 signalosome
NOD2 contributes to the innate immune response. In response to muramyl dipeptide, a breakdown product of peptidoglycan, which is present in the cell wall of bacteria, NOD2 oligomerizes and binds to RIPK2 kinase. Activated TRAF6 together with UBC13-UEV1A (an (E2)-ubiquitin-conjugating complex) then causes ubiquitination of IKBKG (NEMO). Polyubiquitination of IKBKG (NEMO) facilitates the recruitment of the IKK complex to the TAK1 complex. TAK1 then phosphorylates IKBKB to induce IKK complex (IKBKB, CHUK, IKBKG). XIAP, together with BIRC2,3 ubiquitinylates RIPK2 which recruits the LUBAC complex (RBCK1, RNF31, Sharpin) to NOD2. The LUBAC complex then activates the IKK complex via ubiquitinylation. The active IKK complex phosphorylates NFKBIA resulting in ubiquitination and dissociation of NFKBIA from the inactive NF-kappaB complex (NFKB1, NFKB2, REL, RELA, RELB). The activated NF-kappaB then translocates to the nucleus to induce transcription of target genes. Variants of the NOD2 gene are associated with Crohn’s disease. Processes affected by NOD2 signaling and proteins modulating NOD2 signaling are shown in this graph.