Deubiquitinase USP1 influences the dedifferentiation of mouse pancreatic β-cells

Abstract Diabetes is a metabolic disease caused majorly due to loss of insulin secreting β-cells. Along with apoptosis, recent reports revealed dedifferentiation to be the added reason for the reduced β-cell mass. The Ubiquitin Proteasome system comprising of E3 ligase and deubiquitinases (DUBs) control several key aspects of pancreatic β-cell functions. The role of deubiquitinases in orchestrating the dedifferentiation process in several cancers have been well deciphered, but its role in dedifferentiation of pancreatic β-cells remains elusive. In this study, screening for key DUBs that regulate dedifferentiation, identified USP1 to be specifically involved in the process. Inhibition of USP1 either by genetic intervention or small molecule inhibitor ML323 restored epithelial phenotype of β-cells, but not with inhibition of other DUBs. Conversely overexpression of USP1 was sufficient to dedifferentiate β-cells, even in absence of dedifferentiation inducing cues. Mechanistic insight showed USP1 to probably mediate its effect via modulating the expression of Inhibitor of Differentiation (ID) 2. Further, in an in vivo streptozotocin (STZ) induced dedifferentiation mouse model system, treatment with ML323 rescued the hyperglycaemic state. Overall, this study assigns a novel role to USP1 in dedifferentiation of β-cells and its inhibition may have a therapeutic application of reducing the β-cell loss during diabetes.