4.8 Article

Stearic acid blunts growth-factor signaling via oleoylation of GNAI proteins

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NATURE COMMUNICATIONS
卷 12, 期 1, 页码 -

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NATURE PORTFOLIO
DOI: 10.1038/s41467-021-24844-9

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  1. European Research Council (ERC) under the European Union [724286]
  2. Russian Foundation for Basic Research (RFBR) [20-54-12007]
  3. Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [278001972 - TRR 186, 112927078 - TRR 83]
  4. European Research Council (ERC) [724286] Funding Source: European Research Council (ERC)

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This study reveals that exposure of cells to different fatty acids affects the acylation of GNAI proteins, altering their function and EGFR pathway activation, thus linking metabolism to signaling pathways.
Covalent attachment of C16:0 to proteins (palmitoylation) regulates protein function. Proteins are also S-acylated by other fatty acids including C18:0. Whether protein acylation with different fatty acids has different functional outcomes is not well studied. We show here that C18:0 (stearate) and C18:1 (oleate) compete with C16:0 to S-acylate Cys3 of GNAI proteins. C18:0 becomes desaturated so that C18:0 and C18:1 both cause S-oleoylation of GNAI. Exposure of cells to C16:0 or C18:0 shifts GNAI acylation towards palmitoylation or oleoylation, respectively. Oleoylation causes GNAI proteins to shift out of cell membrane detergent-resistant fractions where they potentiate EGFR signaling. Consequently, exposure of cells to C18:0 reduces recruitment of Gab1 to EGFR and reduces AKT activation. This provides a molecular mechanism for the anti-tumor effects of C18:0, uncovers a mechanistic link how metabolites affect cell signaling, and provides evidence that the identity of the fatty acid acylating a protein can have functional consequences. S-acylation is the post-translational covalent attachment of fatty acids (FA) onto cysteines. Nuskova et al. find that exposure of cells to different FAs affects which FA is used to S-acylate GNAI proteins, thereby altering GNAI function and EGFR pathway activation, linking metabolism to signaling.

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