Liu Yujie, Yang Xuechun, Zhou Jian, Yang Haijun, Yang Ruimeng, Zhu Peng, Zhou Rong, Wu Tianyuan, Gao Yongchao, Ye Zhi, Li Xi, Liu Rong, Zhang Wei, Zhou Honghao, Li Qing
Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, China.
Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, 410078, China.
Nat Commun. 2024 Dec 2;15(1):10479. doi: 10.1038/s41467-024-54905-8.
Proinsulin translation and folding is crucial for glucose homeostasis. However, islet β-cell control of Proinsulin translation remains incompletely understood. Here, we identify OSGEP, an enzyme responsible for tA modification of tRNA that tunes glucose metabolism in β-cells. Global Osgep deletion causes glucose intolerance, while β-cell-specific deletion induces hyperglycemia and glucose intolerance due to impaired insulin activity. Transcriptomics and proteomics reveal activation of the unfolded protein response (UPR) and apoptosis signaling pathways in Osgep-deficient islets, linked to an increase in misfolded Proinsulin from reduced tA modification. Osgep overexpression in pancreas rescues insulin secretion and mitigates diabetes in high-fat diet mice. Osgep enhances translational fidelity and alleviates UPR signaling, highlighting its potential as a therapeutic target for diabetes. Individuals carrying the C allele at rs74512655, which promotes OSGEP transcription, may show reduced susceptibility to T2DM. These findings show OSGEP is essential for islet β-cells and a potential diabetes therapy target.
胰岛素原的翻译和折叠对于葡萄糖稳态至关重要。然而，胰岛β细胞对胰岛素原翻译的控制仍未完全了解。在这里，我们鉴定出OSGEP，一种负责tRNA的tA修饰的酶，它可调节β细胞中的葡萄糖代谢。全身性Osgep缺失会导致葡萄糖不耐受，而β细胞特异性缺失则会由于胰岛素活性受损而导致高血糖和葡萄糖不耐受。转录组学和蛋白质组学揭示了Osgep缺陷型胰岛中未折叠蛋白反应（UPR）和细胞凋亡信号通路的激活，这与tA修饰减少导致的错误折叠胰岛素原增加有关。在胰腺中过表达Osgep可挽救胰岛素分泌并减轻高脂饮食小鼠的糖尿病症状。Osgep增强了翻译保真度并减轻了UPR信号传导，突出了其作为糖尿病治疗靶点的潜力。携带rs74512655位点C等位基因（该等位基因可促进OSGEP转录）的个体可能对2型糖尿病的易感性降低。这些发现表明，OSGEP对胰岛β细胞至关重要，是潜在的糖尿病治疗靶点。
