The REG?-proteasome forms a regulatory circuit with I?B? and NF?B in experimental colitis.

ABSTRACT: 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 REG?, a proteasome activator, show significantly attenuated intestinal inflammation and colitis-associated cancer in dextran sodium sulfate model. Bone marrow transplantation experiments suggest that REG?'s function in non-haematopoietic cells primarily contributes to the phenotype. Elevated expression of REG? exacerbates local inflammation and promotes a reciprocal regulatory loop with NF?B involving ubiquitin-independent degradation of I?B?. Additional deletion of I?B? restored colitis phenotypes and inflammatory gene expression in REG?-deficient mice. In sum, this study identifies REG?-mediated control of I?B? as a molecular mechanism that contributes to NF?B activation and promotes bowel inflammation and associated tumour formation in response to chronic injury.

SUBMITTER: Xu J 

PROVIDER: S-EPMC4764899 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature