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Deacetylation Assays to Unravel the Interplay between Sirtuins SIRT2 and Specific Protein-substrates
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SIRT2 and lysine fatty acylation regulate the transforming activity of K-Ras4a

Hui Jing1, Xiaoyu Zhang1, Stephanie A Wisner1

  • 1Department of Chemistry and Chemical Biology, Cornell University, Ithaca, United States.

Elife
|December 15, 2017
PubMed

Insights

This study reveals that lysine fatty acylation regulates K-Ras4a, a Ras GTPase. Sirtuin 2 (SIRT2) removes this modification, impacting cell signaling and potentially cancer development.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Background:

  • Ras proteins are crucial for cell signaling, and their mutations are implicated in various human cancers.
  • Understanding Ras protein regulation is key to developing targeted cancer therapies.

Purpose of the Study:

  • To investigate novel post-translational modifications regulating Ras proteins.
  • To elucidate the role of lysine fatty acylation and Sirtuin 2 (SIRT2) in K-Ras4a function.

Main Methods:

  • Investigated lysine fatty acylation on K-Ras4a, a splice variant of K-Ras.
  • Assessed the enzymatic activity of Sirtuin 2 (SIRT2) in removing fatty acylation from K-Ras4a.
  • Examined the impact of SIRT2-mediated defatty-acylation on K-Ras4a localization and protein interactions.

Main Results:

  • Identified K-Ras4a as a substrate for lysine fatty acylation, a novel regulatory modification.
  • Demonstrated that SIRT2 deacylates K-Ras4a, promoting its localization to endomembranes.
  • Showed that SIRT2-mediated defatty-acylation enhances K-Ras4a interaction with A-Raf, promoting cellular transformation.

Conclusions:

  • Lysine fatty acylation represents a new regulatory mechanism for Ras GTPases, distinct from cysteine fatty acylation.
  • SIRT2-catalyzed lysine defatty-acylation plays a significant role in K-Ras4a-mediated cell signaling and transformation.
Keywords:
K-Rasbiochemistrycell biologylysine fatty acylationnonepost-translational modificationsirtuin

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