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

Author

Listed:
  • Hana Nůsková

    (German Cancer Research Center (DKFZ)
    Heidelberg University)

  • 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)
    Heidelberg University)

  • 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)
    Heidelberg University)

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.

Suggested Citation

  • Hana Nůsková & Marina V. Serebryakova & Anna Ferrer-Caelles & Timo Sachsenheimer & Christian Lüchtenborg & Aubry K. Miller & Britta Brügger & Larisa V. Kordyukova & Aurelio A. Teleman, 2021. "Stearic acid blunts growth-factor signaling via oleoylation of GNAI proteins," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24844-9
    DOI: 10.1038/s41467-021-24844-9
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