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Palmitoylation targets the calcineurin phosphatase to the phosphatidylinositol 4-kinase complex at the plasma membrane

Author

Listed:
  • Idil Ulengin-Talkish

    (Stanford University)

  • Matthew A. H. Parson

    (Department of Biochemistry and Microbiology, University of Victoria)

  • Meredith L. Jenkins

    (Department of Biochemistry and Microbiology, University of Victoria)

  • Jagoree Roy

    (Stanford University)

  • Alexis Z. L. Shih

    (University of British Columbia
    Max-Delbrück Center for Molecular Medicine)

  • Nicole St-Denis

    (University of Toronto
    High-Fidelity Science Communications)

  • Gergo Gulyas

    (National Institutes of Health)

  • Tamas Balla

    (National Institutes of Health)

  • Anne-Claude Gingras

    (University of Toronto
    University of Toronto)

  • Péter Várnai

    (Semmelweis University)

  • Elizabeth Conibear

    (University of British Columbia)

  • John E. Burke

    (Department of Biochemistry and Microbiology, University of Victoria
    The University of British Columbia)

  • Martha S. Cyert

    (Stanford University)

Abstract

Calcineurin, the conserved protein phosphatase and target of immunosuppressants, is a critical mediator of Ca2+ signaling. Here, to discover calcineurin-regulated processes we examined an understudied isoform, CNAβ1. We show that unlike canonical cytosolic calcineurin, CNAβ1 localizes to the plasma membrane and Golgi due to palmitoylation of its divergent C-terminal tail, which is reversed by the ABHD17A depalmitoylase. Palmitoylation targets CNAβ1 to a distinct set of membrane-associated interactors including the phosphatidylinositol 4-kinase (PI4KA) complex containing EFR3B, PI4KA, TTC7B and FAM126A. Hydrogen-deuterium exchange reveals multiple calcineurin-PI4KA complex contacts, including a calcineurin-binding peptide motif in the disordered tail of FAM126A, which we establish as a calcineurin substrate. Calcineurin inhibitors decrease PI4P production during Gq-coupled GPCR signaling, suggesting that calcineurin dephosphorylates and promotes PI4KA complex activity. In sum, this work discovers a calcineurin-regulated signaling pathway which highlights the PI4KA complex as a regulatory target and reveals that dynamic palmitoylation confers unique localization, substrate specificity and regulation to CNAβ1.

Suggested Citation

  • Idil Ulengin-Talkish & Matthew A. H. Parson & Meredith L. Jenkins & Jagoree Roy & Alexis Z. L. Shih & Nicole St-Denis & Gergo Gulyas & Tamas Balla & Anne-Claude Gingras & Péter Várnai & Elizabeth Coni, 2021. "Palmitoylation targets the calcineurin phosphatase to the phosphatidylinositol 4-kinase complex at the plasma membrane," Nature Communications, Nature, vol. 12(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26326-4
    DOI: 10.1038/s41467-021-26326-4
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    References listed on IDEAS

    as
    1. Ruth Hendus-Altenburger & Xinru Wang & Lise M. Sjøgaard-Frich & Elena Pedraz-Cuesta & Sarah R. Sheftic & Anne H. Bendsøe & Rebecca Page & Birthe B. Kragelund & Stine F. Pedersen & Wolfgang Peti, 2019. "Molecular basis for the binding and selective dephosphorylation of Na+/H+ exchanger 1 by calcineurin," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
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