Deubiquitinase USP1 influences the dedifferentiation of mouse pancreatic β-cells

Meenal Francis; Smitha Bhaskar; Saarwani Komanduri; Preethi Sheshadri; Jyothi Prasanna; Anujith Kumar

doi:10.1016/j.isci.2023.106771

Deubiquitinase USP1 influences the dedifferentiation of mouse pancreatic β-cells

iScience. 2023 Apr 26;26(5):106771. doi: 10.1016/j.isci.2023.106771. eCollection 2023 May 19.

Authors

Meenal Francis¹, Smitha Bhaskar¹, Saarwani Komanduri¹, Preethi Sheshadri¹, Jyothi Prasanna¹, Anujith Kumar¹

Affiliation

¹ Manipal Institute of Regenerative Medicine, Bangalore, Manipal Academy of Higher Education, Manipal, India.

Abstract

Loss of insulin-secreting β-cells in diabetes may be either due to apoptosis or dedifferentiation of β-cell mass. The ubiquitin-proteasome system comprising E3 ligase and deubiquitinases (DUBs) controls several aspects of β-cell functions. In this study, screening for key DUBs identified USP1 to be specifically involved in dedifferentiation 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. In absence of dedifferentiation cues, overexpression of USP1 was sufficient to induce dedifferentiation in β-cells; mechanistic insight showed USP1 to mediate its effect via modulating the expression of inhibitor of differentiation (ID) 2. In an in vivo streptozotocin (STZ)-induced dedifferentiation mouse model system, administering ML323 alleviated hyperglycemic state. Overall, this study identifies USP1 to be involved in dedifferentiation of β-cells and its inhibition may have a therapeutic application of reducing β-cell loss during diabetes.

Keywords: Diabetology; Molecular interaction; Specialized functions of cells.