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

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...

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Published ineLife Vol. 6
Main Authors Jing, Hui, Zhang, Xiaoyu, Wisner, Stephanie A, Chen, Xiao, Spiegelman, Nicole A, Linder, Maurine E, Lin, Hening
Format Journal Article
LanguageEnglish
Published England eLife Sciences Publications Ltd 14.12.2017
eLife Sciences Publications, Ltd
Subjects
Acylation
Adenine
Alternative splicing
Biochemistry and Chemical Biology
Cell Biology
Cell cycle
Chemistry
Genetic transformation
K-Ras
K-Ras protein
Localization
Lysine
lysine fatty acylation
Medical research
Mutation
NAD
Nicotinamide
Peptides
Post-translation
post-translational modification
Proteins
Raf protein
sirtuin
Tumor necrosis factor-TNF
Tumors
United States > US
cell biology
K-Ras
sirtuin
biochemistry
lysine fatty acylation
none
post-translational modification
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Summary: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.
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These authors contributed equally to this work.
ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.32436