Protein SUMOylation regulates insulin secretion at multiple stages

Davey, Jeffrey S.; Carmichael, Ruth E.; Craig, Tim J.

Abstract

Type-II Diabetes Mellitus (T2DM) is one of the fastest growing public health issues of modern times, consuming 12% of worldwide health budgets and affecting an estimated 400 million people. A key pathological trait associated with this disease is the failure of normal glucose-stimulated insulin secretion (GSIS) from pancreatic beta cells. Several lines of evidence suggest that vesicle trafficking events such as insulin secretion are regulated by the post-translational modification, SUMOylation, and indeed SUMOylation has been proposed to act as a ‘brake’ on insulin exocytosis. Here, we show that diabetic stimuli which inhibit GSIS are correlated with an increase in cellular protein SUMOylation, and that inhibition of deSUMOylation reduces GSIS. We demonstrate that manipulation of cellular protein SUMOylation levels, by overexpression of several different components of the SUMOylation pathway, have varied and complex effects on GSIS, indicating that SUMOylation regulates this process at multiple stages. We further demonstrate that inhibition of syntaxin1A SUMOylation, via a knockdown-rescue strategy, greatly enhances GSIS. Our data are therefore consistent with the model that SUMOylation acts as a brake on GSIS, and we have identified SUMOylation of syntaxin 1A as a potential component of this brake. However, our data also demonstrates that the role of SUMOylation in GSIS is complex and may involve many substrates.

• Journal Article Type: Article
• Acceptance Date: Jan 21, 2019
• Online Publication Date: Feb 27, 2019
• Publication Date: Feb 27, 2019
• Deposit Date: Jan 31, 2019
• Publicly Available Date: Mar 15, 2019
• Journal: Scientific Reports
• Electronic ISSN: 2045-2322
• Publisher: Nature Research (part of Springer Nature)
• Peer Reviewed: Peer Reviewed
• Volume: 9
• Article Number: 2895
• DOI: https://doi.org/10.1038/s41598-019-39681-6
• Keywords: SUMOylation, insulin, exocytosis, diabetes
• Public URL: https://uwe-repository.worktribe.com/output/851655
• Publisher URL: https://doi.org/10.1038/s41598-019-39681-6
• Contract Date: Jan 31, 2019