The Ubiquitin-Proteasome System (UPS) affects beta-cell survival and function

Abstract

Loss of insulin-producing pancreatic beta-cells is the hallmark of both type 1 diabetes and type 2 diabetes. The mechanism and the components involved in beta-cell death and failure are not yet fully clarified. Identification of key signaling components that promote beta-cell death, understanding their mechanisms of action in detail is crucial in disease pathogenesis as well as for novel therapeutic interventions to halt beta-cell failure during development and progression of diabetes. The ubiquitin-proteasome system (UPS) regulates the stability of many proteins involved in important cellular processes: cell cycle progression, cell differentiation, cell signaling pathways and apoptosis. In this work, I identified two genes within the proteasomal protein control system that are dysregulated in beta-cells under diabetic conditions; F-box protein 28, a substrate recruiting a component of the Skp1-Cul1-F-box (SCF) ligase complex (SCFFBXO28) and the deubiquitinase USP1. Both UPS components have an important function in beta-cell survival in diabetes. F-box only protein 28 (FBXO28) is part of the ubiquitination machinery, namely of the E-3 Ubiquitin Ligase complex that recruits proteins for degradation or for altering their localization or functional activities. My results show that FBXO28 protein levels were reduced under diabetic conditions. Loss of FBXO28 induced beta-cell death, whereas its overexpression improved beta-cell survival, and regulated expression of beta-cell transcription factor NEUROD1 without altering insulin secretion as well as of several beta-cell identity and functional genes. This suggests FBXO28 acts as a pro-survival protein in beta-cells. On the contrary, Ubiquitin-specific protease 1 (USP1), a member of the USP family and a well-known deubiquitinating enzyme (DUB) impairs beta-cell survival in diabetes. USP1 is responsible for removing ubiquitin from substrate proteins and thus influences cellular processes such as survival, differentiation, immunity, and DNA damage response (DDR). Genetic depletion or pharmacological inhibition of USP1 blocked beta-cell death in several experimental models of diabetes in vitro and ex vivo. While DDR signals were elevated in diabetes, USP1 inhibition attenuated the DDR in islets suggesting that the anti-apoptotic action of USP1 inhibition is mediated through suppression of DDR. I have identified a novel function of USP1 in the control of beta-cell survival as potential therapeutic target for the suppression of beta-cell death in diabetes. Taken together, my data highlight the importance of an appropriate expression and activation of ubiquitin-proteasome components for pancreatic beta-cell survival. My results prove that the ubiquitin-proteasome plays a key role in beta-cell survival/failure in diabetes. Further in-depth understanding of the UPS system in beta-cells and establishing its pathways would open up novel approaches towards diabetes therapy.