Deubiquitinase USP1 Influences the Dedifferentiation of Mouse Pancreatic β-cells

Overview

Journal iScience

Publisher Cell Press

Date 2023 May 30

PMID 37250303

Authors

Meenal Francis

Smitha Bhaskar

Saarwani Komanduri

Preethi Sheshadri

Jyothi Prasanna

Anujith Kumar

Affiliations

Soon will be listed here.

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 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.

Citing Articles

Targeting β-Cell Plasticity: A Promising Approach for Diabetes Treatment.

Gojani E, Rai S, Norouzkhani F, Shujat S, Wang B, Li D Curr Issues Mol Biol. 2024; 46(7):7621-7667.

PMID: 39057094 PMC: 11275945. DOI: 10.3390/cimb46070453.

Development, regeneration, and physiological expansion of functional β-cells: Cellular sources and regulators.

Chernysheva M, Ruchko E, Karimova M, Vorotelyak E, Vasiliev A Front Cell Dev Biol. 2024; 12:1424278.

PMID: 39045459 PMC: 11263198. DOI: 10.3389/fcell.2024.1424278.

References

Takkunen M, Grenman R, Hukkanen M, Korhonen M, Garcia de Herreros A, Virtanen I . Snail-dependent and -independent epithelial-mesenchymal transition in oral squamous carcinoma cells. J Histochem Cytochem. 2006; 54(11):1263-75. DOI: 10.1369/jhc.6A6958.2006. View

Fiori J, Shin Y, Kim W, Krzysik-Walker S, Gonzalez-Mariscal I, Carlson O . Resveratrol prevents β-cell dedifferentiation in nonhuman primates given a high-fat/high-sugar diet. Diabetes. 2013; 62(10):3500-13. PMC: 3781448. DOI: 10.2337/db13-0266. View

Chakrabarti L, Wang B, Lee N, Sandler A . A mechanism linking Id2-TGFβ crosstalk to reversible adaptive plasticity in neuroblastoma. PLoS One. 2013; 8(12):e83521. PMC: 3871549. DOI: 10.1371/journal.pone.0083521. View

Hayek A, Lopez A, Beattie G . Enhancement of pancreatic islet cell monolayer growth by endothelial cell matrix and insulin. In Vitro Cell Dev Biol. 1989; 25(2):146-50. DOI: 10.1007/BF02626171. View

Sutherland D, Gruessner R, Kandswamy R, Humar A, Hering B, Gruessner A . Beta-cell replacement therapy (pancreas and islet transplantation) for treatment of diabetes mellitus: an integrated approach. Transplant Proc. 2004; 36(6):1697-9. DOI: 10.1016/j.transproceed.2004.06.069. View

Ghil S, Jeon Y, Suh-Kim H . Inhibition of BETA2/NeuroD by Id2. Exp Mol Med. 2003; 34(5):367-73. DOI: 10.1038/emm.2002.52. View

Hartley T, Brumell J, Volchuk A . Emerging roles for the ubiquitin-proteasome system and autophagy in pancreatic beta-cells. Am J Physiol Endocrinol Metab. 2008; 296(1):E1-10. DOI: 10.1152/ajpendo.90538.2008. View

Liang Q, Dexheimer T, Zhang P, Rosenthal A, Villamil M, You C . A selective USP1-UAF1 inhibitor links deubiquitination to DNA damage responses. Nat Chem Biol. 2014; 10(4):298-304. PMC: 4144829. DOI: 10.1038/nchembio.1455. View

Ventii K, Wilkinson K . Protein partners of deubiquitinating enzymes. Biochem J. 2008; 414(2):161-75. PMC: 2724835. DOI: 10.1042/BJ20080798. View

10.

Nandi D, Tahiliani P, Kumar A, Chandu D . The ubiquitin-proteasome system. J Biosci. 2006; 31(1):137-55. DOI: 10.1007/BF02705243. View

11.

Moin A, Butler A . Alterations in Beta Cell Identity in Type 1 and Type 2 Diabetes. Curr Diab Rep. 2019; 19(9):83. PMC: 6689286. DOI: 10.1007/s11892-019-1194-6. View

12.

Lopez-Avalos M, Duvivier-Kali V, Xu G, Bonner-Weir S, Sharma A, Weir G . Evidence for a role of the ubiquitin-proteasome pathway in pancreatic islets. Diabetes. 2006; 55(5):1223-31. DOI: 10.2337/db05-0450. View

13.

Efrat S . Beta-Cell Dedifferentiation in Type 2 Diabetes: Concise Review. Stem Cells. 2019; 37(10):1267-1272. DOI: 10.1002/stem.3059. View

14.

Voutsadakis I . The ubiquitin-proteasome system and signal transduction pathways regulating Epithelial Mesenchymal transition of cancer. J Biomed Sci. 2012; 19:67. PMC: 3418218. DOI: 10.1186/1423-0127-19-67. View

15.

Sun-Wang J, Yarritu-Gallego A, Ivanova S, Zorzano A . The ubiquitin-proteasome system and autophagy: self-digestion for metabolic health. Trends Endocrinol Metab. 2021; 32(8):594-608. DOI: 10.1016/j.tem.2021.04.015. View

16.

Ibrahim S, Johnson M, Stephens C, Xu J, Moore R, Mariani A . β-Cell pre-mir-21 induces dysfunction and loss of cellular identity by targeting transforming growth factor beta 2 (Tgfb2) and Smad family member 2 (Smad2) mRNAs. Mol Metab. 2021; 53:101289. PMC: 8361274. DOI: 10.1016/j.molmet.2021.101289. View

17.

Cai J, Li M, Wang X, Li L, Li Q, Hou Z . USP37 Promotes Lung Cancer Cell Migration by Stabilizing Snail Protein Deubiquitination. Front Genet. 2020; 10:1324. PMC: 6967296. DOI: 10.3389/fgene.2019.01324. View

18.

Xie Y, Avello M, Schirle M, McWhinnie E, Feng Y, Bric-Furlong E . Deubiquitinase FAM/USP9X interacts with the E3 ubiquitin ligase SMURF1 protein and protects it from ligase activity-dependent self-degradation. J Biol Chem. 2012; 288(5):2976-85. PMC: 3561522. DOI: 10.1074/jbc.M112.430066. View

19.

Zhou H, Liu Y, Zhu R, Ding F, Cao X, Lin D . OTUB1 promotes esophageal squamous cell carcinoma metastasis through modulating Snail stability. Oncogene. 2018; 37(25):3356-3368. DOI: 10.1038/s41388-018-0224-1. View

20.

Sancho R, Gruber R, Gu G, Behrens A . Loss of Fbw7 reprograms adult pancreatic ductal cells into α, δ, and β cells. Cell Stem Cell. 2014; 15(2):139-53. PMC: 4136739. DOI: 10.1016/j.stem.2014.06.019. View