Palmitoylation targets the Calcineurin phosphatase to the Phosphatidylinositol 4-kinase complex at the plasma membrane

Ulengin-Talkish, I.; Parson, M. A.; Jenkins, M. L.; Roy, J.; Shih, A. Z.; St-Denis, N.; Gulyas, G.; Balla, T.; Gingras, A.-C.; Varnai, P.; Conibear, E.; Burke, J. E.; Cyert, M. S.

doi:10.1101/2021.07.14.451536

bioRxiv · 10.1101/2021.07.14.451536

Palmitoylation targets the Calcineurin phosphatase to the Phosphatidylinositol 4-kinase complex at the plasma membrane

Ulengin-Talkish, I.·Parson, M. A.·Jenkins, M. L.·Roy, J.·Shih, A. Z.·St-Denis, N.·Gulyas, G.·Balla, T.·Gingras, A.-C.·Varnai, P.·Conibear, E.·Burke, J. E.·Cyert, M. S.

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Abstract

Calcineurin, the conserved protein phosphatase and target of immunosuppressants, is a critical mediator of Ca2+ signaling. To discover novel calcineurin-regulated processes we examined an understudied isoform, CNA{beta}1. We show that unlike canonical cytosolic calcineurin, CNA{beta}1 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 CNA{beta}1 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 new calcineurin-regulated signaling pathway highlighting the PI4KA complex as a regulatory target and revealing that dynamic palmitoylation confers unique localization, substrate specificity and regulation to CNA{beta}1.

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Ulengin-Talkish, I., Parson, M. A., Jenkins, M. L., Roy, J., Shih, A. Z., St-Denis, N., Gulyas, G., Balla, T., Gingras, A.-C., Varnai, P., Conibear, E., Burke, J. E., Cyert, M. S.. 2021-07-14. Palmitoylation targets the Calcineurin phosphatase to the Phosphatidylinositol 4-kinase complex at the plasma membrane. https://doi.org/10.1101/2021.07.14.451536

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