OSGEP regulates islet β-cell function by modulating proinsulin translation and maintaining ER stress homeostasis in mice
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 O...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2024-12-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-54905-8 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1846137014892625920 |
|---|---|
| author | 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 Qing Li |
| author_facet | 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 Qing Li |
| author_sort | Yujie Liu |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-d0d7ff96412e4b99a9a6554eaecde2c5 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-d0d7ff96412e4b99a9a6554eaecde2c52024-12-08T12:35:23ZengNature PortfolioNature Communications2041-17232024-12-0115111910.1038/s41467-024-54905-8OSGEP regulates islet β-cell function by modulating proinsulin translation and maintaining ER stress homeostasis in miceYujie Liu0Xuechun Yang1Jian Zhou2Haijun Yang3Ruimeng Yang4Peng Zhu5Rong Zhou6Tianyuan Wu7Yongchao Gao8Zhi Ye9Xi Li10Rong Liu11Wei Zhang12Honghao Zhou13Qing Li14Department of Clinical Pharmacology, Xiangya Hospital, Central South UniversityDepartment of Clinical Pharmacology, Xiangya Hospital, Central South UniversityDepartment of Clinical Pharmacology, Xiangya Hospital, Central South UniversityDepartment of Clinical Pharmacology, Xiangya Hospital, Central South UniversityDepartment of Clinical Pharmacology, Xiangya Hospital, Central South UniversityDepartment of Clinical Pharmacology, Xiangya Hospital, Central South UniversityDepartment of Clinical Pharmacology, Xiangya Hospital, Central South UniversityDepartment of Clinical Pharmacology, Xiangya Hospital, Central South UniversityDepartment of Clinical Pharmacology, Xiangya Hospital, Central South UniversityDepartment of Anesthesiology, Xiangya Hospital of Central South UniversityDepartment of Clinical Pharmacology, Xiangya Hospital, Central South UniversityDepartment of Clinical Pharmacology, Xiangya Hospital, Central South UniversityDepartment of Clinical Pharmacology, Xiangya Hospital, Central South UniversityDepartment of Clinical Pharmacology, Xiangya Hospital, Central South UniversityDepartment of Clinical Pharmacology, Xiangya Hospital, Central South UniversityAbstract 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.https://doi.org/10.1038/s41467-024-54905-8 |
| spellingShingle | 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 Qing Li OSGEP regulates islet β-cell function by modulating proinsulin translation and maintaining ER stress homeostasis in mice Nature Communications |
| title | OSGEP regulates islet β-cell function by modulating proinsulin translation and maintaining ER stress homeostasis in mice |
| title_full | OSGEP regulates islet β-cell function by modulating proinsulin translation and maintaining ER stress homeostasis in mice |
| title_fullStr | OSGEP regulates islet β-cell function by modulating proinsulin translation and maintaining ER stress homeostasis in mice |
| title_full_unstemmed | OSGEP regulates islet β-cell function by modulating proinsulin translation and maintaining ER stress homeostasis in mice |
| title_short | OSGEP regulates islet β-cell function by modulating proinsulin translation and maintaining ER stress homeostasis in mice |
| title_sort | osgep regulates islet β cell function by modulating proinsulin translation and maintaining er stress homeostasis in mice |
| url | https://doi.org/10.1038/s41467-024-54905-8 |
| work_keys_str_mv | AT yujieliu osgepregulatesisletbcellfunctionbymodulatingproinsulintranslationandmaintainingerstresshomeostasisinmice AT xuechunyang osgepregulatesisletbcellfunctionbymodulatingproinsulintranslationandmaintainingerstresshomeostasisinmice AT jianzhou osgepregulatesisletbcellfunctionbymodulatingproinsulintranslationandmaintainingerstresshomeostasisinmice AT haijunyang osgepregulatesisletbcellfunctionbymodulatingproinsulintranslationandmaintainingerstresshomeostasisinmice AT ruimengyang osgepregulatesisletbcellfunctionbymodulatingproinsulintranslationandmaintainingerstresshomeostasisinmice AT pengzhu osgepregulatesisletbcellfunctionbymodulatingproinsulintranslationandmaintainingerstresshomeostasisinmice AT rongzhou osgepregulatesisletbcellfunctionbymodulatingproinsulintranslationandmaintainingerstresshomeostasisinmice AT tianyuanwu osgepregulatesisletbcellfunctionbymodulatingproinsulintranslationandmaintainingerstresshomeostasisinmice AT yongchaogao osgepregulatesisletbcellfunctionbymodulatingproinsulintranslationandmaintainingerstresshomeostasisinmice AT zhiye osgepregulatesisletbcellfunctionbymodulatingproinsulintranslationandmaintainingerstresshomeostasisinmice AT xili osgepregulatesisletbcellfunctionbymodulatingproinsulintranslationandmaintainingerstresshomeostasisinmice AT rongliu osgepregulatesisletbcellfunctionbymodulatingproinsulintranslationandmaintainingerstresshomeostasisinmice AT weizhang osgepregulatesisletbcellfunctionbymodulatingproinsulintranslationandmaintainingerstresshomeostasisinmice AT honghaozhou osgepregulatesisletbcellfunctionbymodulatingproinsulintranslationandmaintainingerstresshomeostasisinmice AT qingli osgepregulatesisletbcellfunctionbymodulatingproinsulintranslationandmaintainingerstresshomeostasisinmice |