TY - JOUR
T1 - Deubiquitinase USP1 influences the dedifferentiation of mouse pancreatic β-cells
AU - Francis, Meenal
AU - Bhaskar, Smitha
AU - Komanduri, Saarwani
AU - Sheshadri, Preethi
AU - Prasanna, Jyothi
AU - Kumar, Anujith
N1 - Funding Information:
This study was supported by grants from Indian Council of Medical Research , India (No. 5/4/5-5/Diab/21-NCD-III ) to A.K. Flag-HA-USP1 was a gift from Wade Harper (Addgene plasmid# 22596 ) and pLV-TetO-ID2 was a gift from Hubert Schorle (Addgene plasmid #70764 ). We thank AK lab members for their technical help, suggestions, and encouragement.
Publisher Copyright:
© 2023 The Authors
PY - 2023/5/19
Y1 - 2023/5/19
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85158903907
UR - https://www.scopus.com/pages/publications/85158903907#tab=citedBy
U2 - 10.1016/j.isci.2023.106771
DO - 10.1016/j.isci.2023.106771
M3 - Article
AN - SCOPUS:85158903907
SN - 2589-0042
VL - 26
JO - iScience
JF - iScience
IS - 5
M1 - 106771
ER -
