OSGEP regulates islet β-cell function by modulating proinsulin translation and maintaining ER stress homeostasis in mice

Yujie Liu, Xuechun Yang, Jian Zhou, Haijun Yang, Ruimeng Yang, Peng Zhu, Rong Zhou, Tianyuan Wu, Yongchao Gao, Zhi Ye, Xi Li, Rong Liu, Wei Zhang, Honghao Zhou and Qing Li ()
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Yujie Liu: Central South University
Xuechun Yang: Central South University
Jian Zhou: Central South University
Haijun Yang: Central South University
Ruimeng Yang: Central South University
Peng Zhu: Central South University
Rong Zhou: Central South University
Tianyuan Wu: Central South University
Yongchao Gao: Central South University
Zhi Ye: Xiangya Hospital of Central South University
Xi Li: Central South University
Rong Liu: Central South University
Wei Zhang: Central South University
Honghao Zhou: Central South University
Qing Li: Central South University

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract 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 t6A37 modification of tRNANNU 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 t6A37 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.

Date: 2024
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DOI: 10.1038/s41467-024-54905-8

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