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SIRT6 regulates Ras-related protein R-Ras2 by lysine defatty-acylation
Xiaoyu Zhang1, Nicole A Spiegelman1, Ornella D Nelson1
1Departmeunt of Chemistry and Chemical Biology, Cornell University, Ithaca, United States.
Abstract:
The Ras family of GTPases are important in cell signaling and frequently mutated in human tumors. Understanding their regulation is thus important for studying biology and human diseases. Here, we report that a novel posttranslational mechanism, reversible lysine fatty acylation, regulates R-Ras2, a member of the Ras family. SIRT6, a sirtuin with established tumor suppressor function, regulates the lysine fatty acylation of R-Ras2. In mouse embryonic fibroblasts (MEFs), Sirt6 knockout (KO) increased R-Ras2 lysine fatty acylation. Lysine fatty acylation promotes the plasma membrane localization of R-Ras2 and its interaction with phosphatidylinositol 3-kinase PI3K, leading to activated Akt and increased cell proliferation. Our study establishes lysine fatty acylation as a previously unknown mechanism that regulates the Ras family of GTPases and provides an important mechanism by which SIRT6 functions as a tumor suppressor.
Insights
A new study reveals that reversible lysine fatty acylation regulates R-Ras2, a key cell signaling protein. This finding explains how SIRT6 acts as a tumor suppressor, impacting cancer research.
Area of Science:
- Cellular Biology
- Molecular Biology
- Cancer Research
Background:
- The Ras family of GTPases are crucial in cell signaling pathways.
- Mutations in Ras GTPases are common in human cancers, highlighting the importance of their regulation.
- Understanding Ras GTPase regulation is vital for both fundamental biology and disease research.
Purpose of the Study:
- To investigate novel posttranslational modifications regulating the Ras family of GTPases.
- To elucidate the role of SIRT6 in the regulation of R-Ras2, a specific Ras family member.
- To establish a new mechanism of Ras GTPase regulation and its link to tumor suppression.
Main Methods:
- Utilized mouse embryonic fibroblasts (MEFs) for experimental analysis.
- Performed gene knockout (KO) studies for the Sirt6 gene.
- Investigated protein localization and interactions using biochemical and cell biology techniques.
Main Results:
- Identified reversible lysine fatty acylation as a novel regulatory mechanism for R-Ras2.
- Demonstrated that SIRT6 deficiency (Sirt6 KO) leads to increased R-Ras2 lysine fatty acylation in MEFs.
- Showed that lysine fatty acylation enhances R-Ras2 plasma membrane localization and its interaction with phosphatidylinositol 3-kinase (PI3K).
Conclusions:
- Lysine fatty acylation is a previously unrecognized posttranslational modification controlling Ras GTPase activity.
- SIRT6 regulates R-Ras2 through lysine fatty acylation, contributing to its tumor suppressor function.
- This mechanism provides new insights into cancer biology and potential therapeutic targets.