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

Nat Commun. 2021 Oct 18;12(1):6064. doi: 10.1038/s41467-021-26326-4.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Phosphatidylinositol 4-Kinase / metabolism*
  • Adaptor Proteins, Signal Transducing / metabolism
  • Calcineurin / metabolism
  • Cell Line
  • Cell Membrane / metabolism*
  • Cytoplasm / metabolism
  • Golgi Apparatus / metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins / chemistry
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Lipoylation / physiology*
  • Membrane Proteins / chemistry
  • Membrane Proteins / metabolism
  • Phosphoric Monoester Hydrolases / metabolism*
  • Protein Binding
  • Protein Isoforms / metabolism
  • Signal Transduction / physiology


  • Adaptor Proteins, Signal Transducing
  • EFR3B protein, human
  • FAM126A protein, human
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Protein Isoforms
  • 1-Phosphatidylinositol 4-Kinase
  • calcineurin phosphatase
  • Calcineurin
  • Phosphoric Monoester Hydrolases