2. Academic Validation
  3. Stearic acid blunts growth-factor signaling via oleoylation of GNAI proteins

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

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. a.teleman@dkfz.de.
  • 6 Heidelberg University, Heidelberg, Germany. a.teleman@dkfz.de.
  • # 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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