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

Hana Nůsková, Marina V. Serebryakova, Anna Ferrer-Caelles, Timo Sachsenheimer, Christian Lüchtenborg, Aubry K. Miller, Britta Brügger, Larisa V. Kordyukova and Aurelio A. Teleman ()
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Hana Nůsková: German Cancer Research Center (DKFZ)
Marina V. Serebryakova: A.N. Belozersky Institute of Physico-Chemical Biology, M.V. Lomonosov Moscow State University
Anna Ferrer-Caelles: German Cancer Research Center (DKFZ)
Timo Sachsenheimer: Heidelberg University Biochemistry Center (BZH)
Christian Lüchtenborg: Heidelberg University Biochemistry Center (BZH)
Aubry K. Miller: German Cancer Research Center (DKFZ)
Britta Brügger: Heidelberg University Biochemistry Center (BZH)
Larisa V. Kordyukova: A.N. Belozersky Institute of Physico-Chemical Biology, M.V. Lomonosov Moscow State University
Aurelio A. Teleman: German Cancer Research Center (DKFZ)

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-24844-9

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