SIRT2 and lysine fatty acylation regulate the transforming activity of K-Ras4a

  1. Hui Jing
  2. Xiaoyu Zhang
  3. Stephanie A Wisner
  4. Xiao Chen
  5. Nicole A Spiegelman
  6. Maurine E Linder
  7. Hening Lin  Is a corresponding author
  1. Cornell University, United States
  2. Cornell University College of Veterinary Medicine, United States

Abstract

Ras proteins play vital roles in numerous biological processes and Ras mutations are found in many human tumors. Understanding how Ras proteins are regulated is important for elucidating cell signaling pathways and identifying new targets for treating human diseases. Here we report that one of the K-Ras splice variants, K-Ras4a, is subject to lysine fatty acylation, a previously under-studied protein post-translational modification. Sirtuin 2 (SIRT2), one of the mammalian nicotinamide adenine dinucleotide (NAD)-dependent lysine deacylases, catalyzes the removal of fatty acylation from K-Ras4a. We further demonstrate that SIRT2-mediated lysine defatty-acylation promotes endomembrane localization of K-Ras4a, enhances its interaction with A-Raf, and thus promotes cellular transformation. Our study identifies lysine fatty acylation as a previously unknown regulatory mechanism for the Ras family of GTPases that is distinct from cysteine fatty acylation. These findings highlight the biological significance of lysine fatty acylation and sirtuin-catalyzed protein lysine defatty-acylation.

Article and author information

Author details

  1. Hui Jing

    Department of Chemistry and Chemical Biology, Cornell University, Ithaca, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Xiaoyu Zhang

    Department of Chemistry and Chemical Biology, Cornell University, Ithaca, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0951-9664
  3. Stephanie A Wisner

    Department of Chemistry and Chemical Biology, Cornell University, Ithaca, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Xiao Chen

    Department of Chemistry and Chemical Biology, Cornell University, Ithaca, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Nicole A Spiegelman

    Department of Chemistry and Chemical Biology, Cornell University, Ithaca, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Maurine E Linder

    Department of Molecular Medicine, Cornell University College of Veterinary Medicine, Ithaca, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Hening Lin

    Department of Chemistry and Chemical Biology, Cornell University, Ithaca, United States
    For correspondence
    hl379@cornell.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0255-2701

Funding

National Institutes of Health (1R01GM121540-01A1)

  • Maurine E Linder
  • Hening Lin

Howard Hughes Medical Institute

  • Hui Jing

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Cynthia Wolberger, Johns Hopkins University, United States

Version history

  1. Received: October 2, 2017
  2. Accepted: December 13, 2017
  3. Accepted Manuscript published: December 14, 2017 (version 1)
  4. Version of Record published: December 27, 2017 (version 2)

Copyright

© 2017, Jing et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Hui Jing
  2. Xiaoyu Zhang
  3. Stephanie A Wisner
  4. Xiao Chen
  5. Nicole A Spiegelman
  6. Maurine E Linder
  7. Hening Lin
(2017)
SIRT2 and lysine fatty acylation regulate the transforming activity of K-Ras4a
eLife 6:e32436.
https://doi.org/10.7554/eLife.32436

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https://doi.org/10.7554/eLife.32436

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