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

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.

SUBMITTER: Ulengin-Talkish I

PROVIDER: S-EPMC8523714 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:We report the characterization of two signal transduction proteins related to Bam32, known as TAPP1 and TAPP2. Bam32, TAPP1, and TAPP2 share several characteristics, including small size (32 to 47 kDa), lack of enzymatic domains, high conservation between humans and mice, and the presence of pleckstrin homology (PH) domains near their C termini which contain the 3-phosphoinositide-binding motif. Unlike Bam32, the N-terminal regions of TAPP1 and TAPP2 contain a second PH domain. TAPP1 and TAPP2 transcripts are expressed in a variety of tissues including lymphoid tissues. Using live-cell imaging, we demonstrate that TAPP1 and TAPP2 are recruited to the plasma membrane of BJAB human B-lymphoma cells upon activation through the B-cell antigen receptor (BCR). The C-terminal PH domain is necessary and sufficient for BCR-induced membrane recruitment of both TAPP1 and TAPP2. Blockade of phosphatidylinositol 3-kinase (PI3K) activity completely abolished BCR-induced recruitment of TAPP1 and TAPP2, while expression of active PI3K is sufficient to drive constitutive membrane localization of TAPP1 and TAPP2. TAPP1 and TAPP2 preferentially accumulate within ruffled, F-actin-rich areas of plasma membrane, suggesting a potential role in PI3K-driven cytoskeletal reorganization. Like Bam32, BCR-driven TAPP1 and TAPP2 recruitment is a relatively slow and sustained response, in contrast to Btk recruitment and Ca(2+) mobilization responses, which are rapid and transient. Consistent with recent studies indicating that Bam32, TAPP1, and TAPP2 can bind to PI(3,4)P(2), we find that membrane recruitment correlates well with production of PI(3,4)P(2) but not with that of PI(3,4,5)P(3). Our results indicate that TAPP1 and TAPP2 are direct targets of PI3K signaling that are recruited into plasma membranes with distinctive delayed kinetics and accumulate within F-actin-rich membrane ruffles. We postulate that the TAPPs function to orchestrate cellular responses during the sustained phase of signaling.

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

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