The Function And Mechanism Of Proteasome Activator REGγ In Experimental Colitis And CAC

Inflammatory bowel disease with a lifelong course characterized by periods of remission and relapse, can not be completely cured and there is a trend towards increasing incidence, which demands a better understanding of the molecular mechanisms underlying its multifactorial etiolog.As a member of proteasome activators, REGy can bind to and stimulate 20S proteasome to degrade some important regulatory proteins in non-ubiquitin and non-ATP dependent manner. Here we demonstrate that mice deficient for REGy show significantly attenuated intestinal inflammation in DSS-induced colitis model. Bone marrow transplantation experiments suggest that REGy’s function in non-hematopoietic cells primarily contributes to the phenotype. A series of molecular biological experiments prove there is a reciprocal regulatory loop between REGy and NFkB signaling pathway. REGγ can promote NFkB activation involving ubiquitin-independent degradation of IkBε. And NFkB can directly bind to the promoter of REGy and regulate its expression. Additional deletion of IkBε restores colitis phenotypes and inflammatory gene expression in REGy-deficient mice. In the colitis-associated cancer mice model (AOM/DSS model), REGγ-deficient mice have less tumor number and smaller tumor size than WT mice. In addition, the rescue assay in colitis-associated cancer suggest that IkBε contributes to the protective role against colitis-associated tumorigenesis in REGγ-/- mice by suppressing NFκB activity. Moreover, we demonstrate that higher expression of REGy is positively correlated with UC. However, expression of IkBε and REGy in UC cases have negative correlation. In sum, this study identifies REGy-mediated control of IKBε as an alternative molecular mechanism that contributes to NFKB activation and promotes bowel inflammation and associated tumor formation, and a potential drug target for preventing and treating related diseases.