Dynamics of Ubiquitination in Differentiation and Dedifferentiation of Pancreatic β-cells: Putative Target for Diabetes

Abstract

Impairment in the function of insulin-producing pancreatic β-cells is a hallmark of both type 1 and 2 diabetes (T1D/T2D). Despite nearly a century of efforts to combat acute diabetes burden, there is yet no precise treatment regimen existing. Enhancing the endogenous β-cells either by protecting them from apoptosis or dedifferentiation is a classic alternative approach to retain the β-cell pool. Recent reports have acknowledged the protein homeostasis mediated by the ubiquitin-proteasome system as one of the essential components in maintaining the β-cell pool. Degradation of the targeted substrate by the proteasome is majorly regulated by the ubiquitination status of the targeted protein dictated by E3 ligases and deubiquitinase enzymes. Imbalance in the function of these enzymes results in the malfunction of β-cells and in turn, hyperglycemia. Ubiquitination involves the covalent attachment of one or more ubiquitin moieties to the target protein by E3 ubiquitin ligases and deubiquitinases (DUBs) are the enzymes which antagonize the action of E3 ligases. Having knowledge about different E3 ligases and deubiquitinases in the process of differentiation and dedifferentiation of β-cells, probably paves the way for designing novel modulators that enhance either the differentiation or abate the dedifferentiation process. In this review, we will discuss the importance of the balanced ubiquitination process, an understanding of which would facilitate the restraining of β-cells from exhaustion.

Deubiquitinase USP1 influences the dedifferentiation of mouse pancreatic β-cells

“…To date, there has been an ongoing debate on whether β-cells per se undergo dedifferentiation or the mesenchymal cells exist from the pre-existing mesenchymal cells, or is it the transdifferentiation of other islet cells (Francis et al, 2022). Though the ambiguity persists till date, several lineage tracing studies including the elegant study by Talchai et.…”