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

Uncontrolled inflammation in the gut is one of the major cause for development of inflammatory bowel disease (IBD), a chronic form of autoimmune disorder. Ulcerative colitis (UC) and Crohn’s disease (CD) are the two common forms of IBD involving intestinal distress with varied manifestations resulting in severely compromised patient lifestyles. More importantly in the recent times there has been a sudden upsurge in incidences of IBD.  Inflammation in IBD occurs due a breakdown in epithelial barrier and a dysregulated epithelial signaling.   The current therapies of IBD relies on immune suppressive strategies resulting in limited prognosis and unwanted side effects. Activation of aberrant signaling pathways that trigger recurrent inflammation in IBD are not well understood. Post-translation modification (PTM), particularly SUMOylation is now being recognized to be responsible for modulation of several fundamental biological processes. SUMOylation status of cell is governed by a concerted action of SUMOylation-pathway components and deSUMOylase enzymes. Using a mutli-pronged methodology, in a quest to understand the epithelial-immunocyte signaling in IBD, we probed possible role of epithelial SUMOylation machinery in triggering inflammation. We used cell culture, murine model of IBD and human IBD patient biopsy samples in this study. Results revealed that the inflammatory cascade was tightly linked to the SUMOylation status of the epithelial cells. Specifically we observed significant upregulation of deSUMOylase machinery enzyme SENP7 in DSS treated IBD mice model and human IBD patient’s samples. This led us to explore the SENP7 interactome during colitis. A proteome analysis identified several crucial regulators and proteins found to be linked with pathways like TNF signaling, IFN signaling and apoptosis in inflamed tissue. Our analysis revealed E3 Ubiquitin ligase SIAH2 regulates SENP7 stability via ubiquitin mediated degradation in healthy epithelial cells, but not in inflamed cells. These changes in the epithelium were accompanied with a dramatic expansion of γδ T cells in lymphoid organs. Using in vitro co-culture models we have shown SENP7 epithelial upregulation was sufficient to trigger proliferation of γδ T cells consequential in a pro-inflammatory environment.  In vivo SENP7 suppression result in mice recovery from DSS colitis along with reduction in γδ T cells population. Together this work, a first of its kind, points towards a crucial role for deSUMOylase SENP7 in controlling intestinal inflammation in IBD.

FIGURE: Model depicting SUMOylation dependent epithelial signaling in healthy and inflamed intestine. Image courtesy: For full article: Cell Reports 29, 3522–3538December 10, 2019

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