Kanaka Durga Devi Gorrepati
An SCFfbxo28 E3 ligase protects pancreatic β-cells from apoptosis
Gorrepati, Kanaka Durga Devi; He, Wei; Lupse, Blaz; Yuan, Ting; Maedler, Kathrin; Ardestani, Amin
Authors
Wei He
Blaz Lupse
Ting Yuan
Kathrin Maedler
Dr Amin Ardestani A.Ardestani@hull.ac.uk
Senior Lecturer
Abstract
Loss of pancreatic β-cell function and/or mass is a central hallmark of all forms of diabetes but its molecular basis is incompletely understood. β-cell apoptosis contributes to the reduced β-cell mass in diabetes. Therefore, the identification of important signaling molecules that promote β-cell survival in diabetes could lead to a promising therapeutic intervention to block β-cell decline during development and progression of diabetes. In the present study, we identified F-box protein 28 (FBXO28), a substrate-recruiting component of the Skp1-Cul1-F-box (SCF) ligase complex, as a regulator of pancreatic β-cell survival. FBXO28 was down-regulated in β-cells and in isolated human islets under diabetic conditions. Consistently, genetic silencing of FBXO28 impaired β-cell survival, and restoration of FBXO28 protected β-cells from the harmful effects of the diabetic milieu. Although FBXO28 expression positively correlated with β-cell transcription factor NEUROD1 and FBXO28 depletion also reduced insulin mRNA expression, neither FBXO28 overexpression nor depletion had any significant impact on insulin content, glucose-stimulated insulin secretion (GSIS) or on other genes involved in glucose sensing and metabolism or on important β-cell transcription factors in isolated human islets. Consistently, FBXO28 overexpression did not further alter insulin content and GSIS in freshly isolated islets from patients with type 2 diabetes (T2D). Our data show that FBXO28 improves pancreatic β-cell survival under diabetogenic conditions without affecting insulin secretion, and its restoration may be a novel therapeutic tool to promote β-cell survival in diabetes.
Citation
Gorrepati, K. D. D., He, W., Lupse, B., Yuan, T., Maedler, K., & Ardestani, A. (2018). An SCFfbxo28 E3 ligase protects pancreatic β-cells from apoptosis. International Journal of Molecular Sciences, 19(4), Article 975. https://doi.org/10.3390/ijms19040975
Journal Article Type | Article |
---|---|
Acceptance Date | Mar 22, 2018 |
Online Publication Date | Mar 24, 2018 |
Publication Date | Apr 1, 2018 |
Deposit Date | Jan 4, 2024 |
Publicly Available Date | Jan 5, 2024 |
Journal | International Journal of Molecular Sciences |
Electronic ISSN | 1422-0067 |
Publisher | MDPI |
Peer Reviewed | Peer Reviewed |
Volume | 19 |
Issue | 4 |
Article Number | 975 |
DOI | https://doi.org/10.3390/ijms19040975 |
Keywords | Pancreatic β-cell; Diabetes; Human islet; Apoptosis; FBXO28; Insulin secretion; NeuroD1; E3 ligase |
Public URL | https://hull-repository.worktribe.com/output/4461631 |
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Copyright Statement
© 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
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