SUMOylation pathway alteration coupled with downregulation of SUMO E2 enzyme at mucosal epithelium modulates inflammation in inflammatory bowel disease

Abstract

Post-translational modification pathways such as SUMOylation are integral to all cellular processes and tissue homeostasis. We investigated the possible involvement of SUMOylation in the epithelial signalling in Crohn's disease (CD) and ulcerative colitis (UC), the two major forms of inflammatory bowel disease (IBD). Initially in a murine model of IBD, induced by dextran–sulfate–sodium (DSS mice), we observed inflammation accompanied by a lowering of global SUMOylation of colonic epithelium. The observed SUMOylation alteration was due to a decrease in the sole SUMO E2 enzyme (Ubc9). Mass-spectrometric analysis revealed the existence of a distinct SUMOylome (SUMO-conjugated proteome) in DSS mice with alteration of key cellular regulators, including master kinase Akt1. Knocking-down of Ubc9 in epithelial cells resulted in dramatic activation of inflammatory gene expression, a phenomenon that acted via reduction in Akt1 and its SUMOylated form. Importantly, a strong decrease in Ubc9 and Akt1 was also seen in endoscopic biopsy samples (N = 66) of human CD and UC patients. Furthermore, patients with maximum disease indices were always accompanied by severely lowered Ubc9 or SUMOylated-Akt1. Mucosal tissues with severely compromised Ubc9 function displayed higher levels of pro-inflammatory cytokines and compromised wound-healing markers. Thus, our results reveal an important and previously undescribed role for the SUMOylation pathway involving Ubc9 and Akt1 in modulation of epithelial inflammatory signalling in IBD.

A SUMOylation dependent switch of Rab7 governs intracellular life and pathogenesis of Salmonella Typhimurium

“…DeSUMOylation involves several cysteine proteases also called deSUMOylases or sentrinspecific proteases (SENPs). SUMOylation processes act as molecular switches allowing proteins to carry out a variety of functions (Flotho and Melchior, 2013;Mustfa et al, 2017). In an earlier work, we reported SUMOylation to be important for S. Typhimurium infection (Verma et al, 2015), although its exact role in the intracellular life of the bacteria remains unexplored.…”

Resveratrol Attenuates Inflammatory Bowel Disease in Mice by Regulating SUMO1

“…12,13) Based on the characteristics of SUMO1, it plays an important role in many diseases such as inflammation-related diseases, tumors, and kidney diseases. [14][15][16] In our study, we researched the role of resveratrol in inhibiting the expression of SUMO1 and the Wnt/β-catenin pathway in dextran sodium sulfate (DSS)-induced IBD. Furthermore, the expression of SUMO1 in different processes of human colorectal cancer development was examined.…”

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

“…This may be attributed to the versatility, dynamicity, and reversibility of SUMOylation. Several reports from our group and others have highlighted the importance of SUMOylation in gut inflammation (Verma et al, 2015;Fritah et al, 2014;Mustfa et al, 2017). The reversibility of SUMOylation is achieved by deconjugation of SUMOylated protein by the action of deSUMOylases, a set of cysteine proteases that are also referred as SUMO-specific proteases or SUMO isopeptidases (Yeh et al, 2000).…”