DeSUMOylase SENP7-Mediated Epithelial Signaling Triggers Intestinal Inflammation via Expansion of Gamma-Delta T Cells

Abstract

Summary: Inflammatory bowel disease (IBD) is a complex autoimmune disorder recently shown to be associated with SUMOylation, a post-translational modification mechanism. Here, we have identified a link between epithelial deSUMOylases and inflammation in IBD. DeSUMOylase SENP7 was seen to be upregulated specifically in intestinal epithelial cells in both human IBD and a mouse model. In steady state, but not IBD, SENP7 expression was negatively regulated by a direct interaction and ubiquitination by SIAH2. Upregulated SENP7 in inflamed tissue displayed a distinct interactome. These changes led to an expansion of localized proinflammatory γδ T cells. Furthermore, in vivo knockdown of SENP7 or depletion of γδ T cells abrogated dextran sulfate sodium (DSS)-induced gut inflammation. Strong statistical correlations between upregulated SENP7 and high clinical disease indices were observed in IBD patients. Overall, our data reveal that epithelial SENP7 is necessary and sufficient for controlling gut inflammation, thus highlighting its importance as a potential drug target. : DeSUMOylases are contributors to cellular physiology and disease. Here, Suhail et al. demonstrate an aberrant epithelial upregulation of the deSUMOylase SENP7, leading to expansion of proinflammatory γδT cells during inflammatory bowel disease. Experimental inhibition of SENP7 was sufficient to tame inflammation, thus demonstrating therapeutic potential. Keywords: inflammation, deSUMOylases, PTMs, SUMOylation, proteomics, gut, IBD, gamma delta T cells, SENPs