2023 Fiscal Year Final Research Report
Pre-emptive protein quality control machinery-mediated regulation of Rab8-family small GTPases
| Project/Area Number |
20H00457
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Review Section |
Medium-sized Section 43:Biology at molecular to cellular levels, and related fields
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| Research Institution | Tokyo Metropolitan University |
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Principal Investigator |
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| Project Period (FY) |
2020-04-01 – 2024-03-31
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| Keywords | Protein quality control / ubiquitin / small GTPase / BAG6 / RNF126 / Rab8 / ciliogenesis / proteasome |
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| Outline of Final Research Achievements |
The small GTPase Rab8 plays a vital role in the vesicular trafficking of cargo proteins from the trans-Golgi network to target membranes. Upon reaching its target destination, Rab8 is released from the vesicular membrane into the cytoplasm. The fate of GDP-bound Rab8 released from the destination membranes, however, has not been investigated adequately. In this study, we found that GDP-bound Rab8 subfamily proteins are targeted for immediate degradation, and the pre-emptive quality control machinery is essential for eliminating these proteins in a nucleotide-specific manner. We provide evidence that components of this quality control machinery have a critical role in vesicular trafficking events, including the formation of primary cilia, a process regulated by the Rab8 subfamily. These results suggest that the protein degradation machinery plays a critical role in the integrity of membrane trafficking by limiting the excessive accumulation of GDP-bound Rab8 subfamily proteins.
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| Free Research Field |
生化学・細胞生物学
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| Academic Significance and Societal Importance of the Research Achievements |
ヒトの細胞内には、物質輸送のネットワークが張り巡らされています。このシステムは、RabやRhoといった一群の低分子量Gタンパク質によって調節されていますが、これらタンパク質の活性や存在量がどのように規定されるかはわかっていませんでした。本研究により、プレエンプティヴ品質管理と呼ばれるタンパク質分解マシナリーが、低分子量Gタンパク質Rab8a, Rab10,およびRhoAの安定性を制御していること、これらを介して細胞内物質輸送や細胞骨格の構築が守られていることを初めて明らかにしました。これらの成果は、アメリカ細胞生物学会誌などに掲載され、注目を集めています。
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