An SCFfbxo28 E3 ligase protects pancreatic β-cells from apoptosis

Gorrepati, Kanaka Durga Devi; He, Wei; Lupse, Blaz; Yuan, Ting; Maedler, Kathrin; Ardestani, Amin

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