The REGγ 3-proteasome forms a regulatory circuit with Iκ BIκ and NFκB in experimental colitis

Increasing incidence of inflammatory bowel disorders demands a better understanding of the molecular mechanisms underlying its multifactorial aetiology. Here we demonstrate that mice deficient for REGI 3, a proteasome activator, show significantly attenuated intestinal inflammation and colitis-Associated cancer in dextran sodium sulfate model. Bone marrow transplantation experiments suggest that REGI 3â € s function in non-haematopoietic cells primarily contributes to the phenotype. Elevated expression of REGI 3 exacerbates local inflammation and promotes a reciprocal regulatory loop with NFI° B involving ubiquitin-independent degradation of II° BI>. Additional deletion of II° BI> restored colitis phenotypes and inflammatory gene expression in REGI 3-deficient mice. In sum, this study identifies REGI 3-mediated control of II° BI> as a molecular mechanism that contributes to NFI° B activation and promotes bowel inflammation and associated tumour formation in response to chronic injury.