An SCFFBXO28 E3 Ligase Protects Pancreatic ß-Cells from Apoptosis.

Loss of pancreatic ß-cell function and/or mass is a central hallmark of all forms of diabetes but its molecular basis is incompletely understood. ß-cell apoptosis contributes to the reduced ß-cell mass in diabetes. Therefore, the identification of important signaling molecules that promote ß-cell survival in diabetes could lead to a promising therapeutic intervention to block ß-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 ß-cell survival. FBXO28 was down-regulated in ß-cells and in isolated human islets under diabetic conditions. Consistently, genetic silencing of FBXO28 impaired ß-cell survival, and restoration of FBXO28 protected ß-cells from the harmful effects of the diabetic milieu. Although FBXO28 expression positively correlated with ß-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 ß-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 ß-cell survival under diabetogenic conditions without affecting insulin secretion, and its restoration may be a novel therapeutic tool to promote ß-cell survival in diabetes.