1. Academic Validation
  2. SIRT2 and lysine fatty acylation regulate the transforming activity of K-Ras4a

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

  • Elife. 2017 Dec 14:6:e32436. doi: 10.7554/eLife.32436.
Hui Jing # 1 Xiaoyu Zhang # 1 Stephanie A Wisner 1 Xiao Chen 1 Nicole A Spiegelman 1 Maurine E Linder 2 Hening Lin 1 3
Affiliations

Affiliations

  • 1 Department of Chemistry and Chemical Biology, Cornell University, Ithaca, United States.
  • 2 Department of Molecular Medicine, Cornell University College of Veterinary Medicine, Ithaca, United States.
  • 3 Department of Chemistry and Chemical Biology, Howard Hughes Medical Institute, Cornell University, Ithaca, United States.
  • # Contributed equally.
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.

Keywords

K-Ras; biochemistry; cell biology; lysine fatty acylation; none; post-translational modification; sirtuin.

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