Palmitoylation Targets the Calcineurin Phosphatase to the Phosphatidylinositol 4‐kinase Complex at the Plasma Membrane

Autor: Elizabeth Conibear, Tamas Balla, Péter Várnai, Meredith L. Jenkins, Anne-Claude Gingras, Matthew A.H. Parson, Nicole St-Denis, John E. Burke, Idil Ulengin-Talkish, Gergo Gulyas, Alexis Z. L. Shih, Martha S. Cyert, Jagoree Roy
Rok vydání: 2022
Předmět:
Cytoplasm
Science
Lipoylation
Phosphatase
General Physics and Astronomy
Golgi Apparatus
Biochemistry
General Biochemistry
Genetics and Molecular Biology
Cell Line
03 medical and health sciences
chemistry.chemical_compound
symbols.namesake
0302 clinical medicine
Palmitoylation
Genetics
Humans
Protein Isoforms
Phosphatidylinositol
1-Phosphatidylinositol 4-Kinase
Molecular Biology
030304 developmental biology
Adaptor Proteins
Signal Transducing
0303 health sciences
Multidisciplinary
Kinase
Calcineurin
Cell Membrane
Intracellular Signaling Peptides and Proteins
Membrane Proteins
General Chemistry
Golgi apparatus
Phosphoric Monoester Hydrolases
3. Good health
Cell biology
chemistry
symbols
lipids (amino acids
peptides
and proteins)
Signal transduction
030217 neurology & neurosurgery
PI4KA
Protein Binding
Signal Transduction
Biotechnology
Zdroj: Nature Communications, Vol 12, Iss 1, Pp 1-19 (2021)
ISSN: 1530-6860
0892-6638
Popis: 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.
Databáze: OpenAIRE
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