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

  • Nat Commun. 2021 Jul 28;12(1):4590. doi: 10.1038/s41467-021-24844-9.
Hana Nůsková  1  2 ,  Marina V Serebryakova  #  3 ,  Anna Ferrer-Caelles  #  1  2 ,  Timo Sachsenheimer  4 ,  Christian Lüchtenborg  4 ,  Aubry K Miller  1 ,  Britta Brügger  4 ,  Larisa V Kordyukova  3 ,  Aurelio A Teleman  5  6
Affiliations
  • 1. German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 2. Heidelberg University, Heidelberg, Germany.
  • 3. A.N. Belozersky Institute of Physico-Chemical Biology, M.V. Lomonosov Moscow State University, Moscow, Russia.
  • 4. Heidelberg University Biochemistry Center (BZH), Heidelberg, Germany.
  • 5. German Cancer Research Center (DKFZ), Heidelberg, Germany. [email protected].
  • 6. Heidelberg University, Heidelberg, Germany. [email protected].
  • # Contributed equally.
PMID: 34321466 DOI: 10.1038/s41467-021-24844-9
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.

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