SIRT6 regulates Ras-related protein R-Ras2 by lysine defatty-acylation
| Autor: | Hui Jing, Ornella D. Nelson, Xiaoyu Zhang, Hening Lin, Nicole A Spiegelman |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
SIRT6 QH301-705.5 Science Acylation Cell Lysine complex mixtures Biochemistry General Biochemistry Genetics and Molecular Biology 03 medical and health sciences chemistry.chemical_compound Mice medicine Animals Sirtuins Biology (General) Mice Knockout General Immunology and Microbiology biology General Neuroscience Cancer General Medicine Cell Biology Fibroblasts medicine.disease 3. Good health sirtuin 030104 developmental biology medicine.anatomical_structure chemistry Cancer cell Sirtuin biology.protein ras Proteins Medicine bacteria Protein Processing Post-Translational Acyl group Research Article Ras defatty-acylation |
| Zdroj: | eLife eLife, Vol 6 (2017) |
| ISSN: | 2050-084X |
| Popis: | 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. DOI: http://dx.doi.org/10.7554/eLife.25158.001 eLife digest Cancer is one of the leading causes of death worldwide. Proteins that cause and promote cancer are called oncoproteins. Other proteins, called tumor suppressors, counteract the oncoproteins but are frequently inactive or not present in cancer cells. SIRT6 is a tumor suppressor protein that has been studied in many different types of cancer. In 2013, researchers found that SIRT6 can remove chemical groups known as fatty acyl groups from the lysine residues of proteins. However, it was unclear whether and how this activity of SIRT6 contributes to its role as a tumor suppressor. Zhang et al. – who are part of the research group who performed the 2013 study – have now compared mouse cells that lack SIRT6 with normal mouse cells to find out which proteins SIRT6 removes fatty acyl groups from. A biochemical technique that makes use of synthetic fatty acids, which get incorporated into the mouse cells, showed that SIRT6 removes fatty acyl groups from a protein called R-Ras2. This protein is part of a large family of oncoproteins. Zhang et al. discovered that when R-Ras2 is tagged with the fatty acyl group it moves to the cell’s membrane and causes the cell to divide more rapidly. Hence, this promotes the growth and spread of cancerous tumors. SIRT6 acts as an eraser, removing the fatty acyl group, and therefore slows down the growth of cancer cells. Future experiments will aim to find out whether fatty acyl groups also control the activity of other oncoproteins that are similar to R-Ras2. If that is the case, drugs that can regulate the removal of fatty acyl groups from oncoproteins may eventually form new cancer treatment options. DOI: http://dx.doi.org/10.7554/eLife.25158.002 |
| Databáze: | OpenAIRE |
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