Restored UBE2C expression in islets promotes β-cell regeneration in mice by ubiquitinating PER1
Restored UBE2C expression in islets promotes β-cell regeneration in mice by ubiquitinating PER1
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DOI：
10.1007/s00018-023-04868-8
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发表时间：
2023-07
影响因子：
8
通讯作者：
Hemin Jiang;Shuai Zheng;Yu Qian;Yuncai Zhou;H. Dai;Yucheng Liang;Yunqiang He;R. Gao;Hui Lv;Jie Zhang;Zhiqing Xia;Wen Bian;T. Yang;Qi Fu
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作者：
Hemin Jiang;Shuai Zheng;Yu Qian;Yuncai Zhou;H. Dai;Yucheng Liang;Yunqiang He;R. Gao;Hui Lv;Jie Zhang;Zhiqing Xia;Wen Bian;T. Yang;Qi Fu
胰岛素缺乏可能是由于胰岛β细胞增殖能力降低，导致糖尿病的发生。因此，研究胰岛β细胞再生的机制是十分必要的。NKX6.1是β细胞的关键转录因子之一，是β细胞增殖的关键因子。泛素结合酶2C （UBE2C）是NKX6.1的下游分子之一，但UBE2C在β细胞中的确切功能和机制尚不清楚。在这里，我们确定了一个高度表达UBE2C的胰岛β细胞亚群，它们增殖活跃。我们还发现UBE2C通过细胞周期更新途径诱导断奶小鼠和高脂饮食（HFD）喂养小鼠β细胞代偿性增殖。此外，β细胞增殖的减少导致βUbe2cKO小鼠胰岛素缺乏，从而发展为2型糖尿病。研究发现UBE2C通过与泛素连接酶CUL1的关联，通过泛素-蛋白酶体途径调节PER1的降解。PER1抑制可在体内和体外恢复UBE2C敲除诱导的β细胞生长抑制。值得注意的是，通过慢病毒转导在胰岛中过表达UBE2C能够在stz诱导的糖尿病小鼠中重新启动β细胞增殖，从而部分缓解高血糖和葡萄糖耐受不良。本研究表明，UBE2C通过促进泛素化和生物钟抑制因子PER1的降解，积极调节β-细胞增殖。UBE2C对胰岛β细胞再生的有益作用提示其在治疗伴有β细胞缺乏症的糖尿病患者中的应用前景。图形抽象
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.Graphical abstract