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Restored UBE2C expression in islets promotes β-cell regeneration in mice by ubiquitinating PER1

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Abstract

Insulin deficiency may be due to the reduced proliferation capacity of islet β-cell, contributing to the onset of diabetes. It is therefore imperative to investigate the mechanism of the β-cell regeneration in the islets. NKX6.1, one of the critical β-cell transcription factors, is a pivotal element in β-cell proliferation. The ubiquitin-binding enzyme 2C (UBE2C) was previously reported as one of the downstream molecules of NKX6.1 though the exact function and mechanism of UBE2C in β-cell remain to be elucidated. Here, we determined a subpopulation of islet β-cells highly expressing UBE2C, which proliferate actively. We also discovered that β-cell compensatory proliferation was induced by UBE2C via the cell cycle renewal pathway in weaning and high-fat diet (HFD)-fed mice. Moreover, the reduction of β-cell proliferation led to insulin deficiency in βUbe2cKO mice and, therefore, developed type 2 diabetes. UBE2C was found to regulate PER1 degradation through the ubiquitin–proteasome pathway via its association with a ubiquitin ligase, CUL1. PER1 inhibition rescues UBE2C knockout-induced β-cell growth inhibition both in vivo and in vitro. Notably, overexpression of UBE2C via lentiviral transduction in pancreatic islets was able to relaunch β-cell proliferation in STZ-induced diabetic mice and therefore partially alleviated hyperglycaemia and glucose intolerance. This study indicates that UBE2C positively regulates β-cell proliferation by promoting ubiquitination and degradation of the biological clock suppressor PER1. The beneficial effect of UBE2C on islet β-cell regeneration suggests a promising application in treating diabetic patients with β-cell deficiency.

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Data availability

The scRNA-seq analysis datasets during the current study are available in the Gene Expression Omnibus (GEO) repository under the accession number GSE203376 (mouse) and GSE148073 (human). Other datasets are available from the corresponding author upon reasonable request.

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Acknowledgements

The authors wish to thank all research staff in Department of Endocrinology of the First Affiliated Hospital of Nanjing Medical University who participated in this work. They would like to thank the Core Facility of the First Affiliated Hospital of Nanjing Medical University for its help in the experiment. They would like to thank Professor Hongxing Fu from Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College for providing the human pancreas slice samples.

Funding

This work was supported by the National Natural Science Foundation of China (81830023, 82070803 and 82100837).

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  1. Hemin Jiang, Shuai Zheng, Yu Qian and Yuncai Zhou are contribute equally to this work and share co-first authorship.

Authors and Affiliations

  1. Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China

    Hemin Jiang, Shuai Zheng, Yu Qian, Yuncai Zhou, Hao Dai, Yucheng Liang, Yunqiang He, Rui Gao, Hui Lv, Jie Zhang, Zhiqing Xia, Wenxuan Bian, Tao Yang & Qi Fu

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Contributions

QF and TY directed the study and were responsible for study design and overall project management. HJ, SZ, YQ and YZ performed statistical analyses, participated in study design, and drafted the manuscript. HD, YL, YZ, YH, JZ, ZX, and RG analysed the data. HL, WB, and KX contributed to conception, design, and interpretation of this work. All the authors approved the final manuscript.

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Correspondence to Tao Yang or Qi Fu.

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The authors declare no competing financial interests.

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Animal use procedures were approved (IACUC1804001) by the Medicine Animal Care Committee of Nanjing Medical University. Experiments were conducted in accordance with relevant institutional guidelines and regulations.

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Jiang, H., Zheng, S., Qian, Y. et al. Restored UBE2C expression in islets promotes β-cell regeneration in mice by ubiquitinating PER1. Cell. Mol. Life Sci. 80, 226 (2023). https://doi.org/10.1007/s00018-023-04868-8

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