2021 Fiscal Year Final Research Report
Post-transcriptional regulation in glucose-induced insulin secretion by the CCR4-NOT deadenylase complex in mouse pancreatic beta cells
| Project/Area Number |
18K06975
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 49010:Pathological biochemistry-related
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| Research Institution | Okinawa Institute of Science and Technology Graduate University |
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Principal Investigator |
Yanagiya Akiko 沖縄科学技術大学院大学, 細胞シグナルユニット, スタッフサイエンティスト (30608138)
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| Project Period (FY) |
2018-04-01 – 2022-03-31
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| Keywords | 転写後制御 / mRNA分解 / 脱アデニル化 / CCR4-NOT複合体 / インスリン生合成 / 膵β細胞 |
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| Outline of Final Research Achievements |
Pancreatic islets isolated from Cnot7-knockout (KO) mice lacking CNOT7, which is a component possessing deadenylase activity of the CCR4-NOT complex, were used to reveal the role of the post-transcriptional regulation by the CCR4-NOT complex in glucose-induced insulin secretion in pancreatic β cells. Intriguingly, glucose-induced insulin secretion is reduced in Cnot7-KO pancreatic β cells. To investigate the contribution of the CCR4-NOT complex in mRNA stability in pancreatic islets, transcriptome and proteome analyses were conducted by RNA-seq and mass spectrometry, which revealed that a peroxiredoxin called PRDX4, which is important for the formation of disulfide bonds inside insulin, is reduced at both mRNA and protein levels. Furthermore, RNA-binding protein that recruits the CCR4-NOT complex to Prdx4 mRNA was identified. Our study sheds light on the post-transcriptional regulation by the CCR4-NOT complex needed for insulin biosynthesis and subsequent insulin secretion.
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| Free Research Field |
転写後制御
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| Academic Significance and Societal Importance of the Research Achievements |
本研究は、CCR4-NOT複合体を介した転写後制御がインスリン生合成において重要な役割を担うことを明らかにした。Cnot7欠損またはCnot8欠損マウスは異なる表現型を示すが、CCR4-NOT複合体の脱アデニル化活性を持つ構成分子であるCNOT7とCNOT8はアミノ酸配列の相同性から、機能的に相補的に働くと考えられていた。本研究によりCNOT7とCNOT8が異なるRNA結合蛋白質を介して、CCR4-NOT複合体を特異的なmRNAに導入し、mRNA分解を行うという分子機構を明らかにした。本研究は、転写後制御を標的としたインスリン生合成や分泌が低下している糖尿病に対する新規治療法の開発に役立つ。
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