DeSUMOylase SENP7-Mediated Epithelial Signaling Triggers Intestinal Inflammation via Expansion of Gamma-Delta T Cells
| Autor: | Aamir Suhail, Prabhakar Mujagond, Preksha Gaur, Vineet Ahuja, C. V. Srikanth, Mukesh Singh, Syed Azmal Ali, Amit Awasthi, Zaigham Abbas Rizvi |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Adult
Male 0301 basic medicine SUMO protein Inflammation SIAH2 digestive system Inflammatory bowel disease General Biochemistry Genetics and Molecular Biology Proinflammatory cytokine Mice 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Ubiquitin Cell Line Tumor Endopeptidases medicine Animals Humans Intestinal Mucosa Intraepithelial Lymphocytes lcsh:QH301-705.5 Gene knockdown biology Chemistry Middle Aged Inflammatory Bowel Diseases medicine.disease digestive system diseases Up-Regulation Cell biology Mice Inbred C57BL 030104 developmental biology lcsh:Biology (General) biology.protein Female medicine.symptom 030217 neurology & neurosurgery Signal Transduction |
| Zdroj: | Cell Reports, Vol 29, Iss 11, Pp 3522-3538.e7 (2019) |
| ISSN: | 2211-1247 |
| Popis: | 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 |
| Databáze: | OpenAIRE |
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