Palmitoylation Targets the Calcineurin Phosphatase to the Phosphatidylinositol 4‐kinase Complex at the Plasma Membrane
Bibliographic record
Abstract
Calcineurin (CN), the serine/threonine protein phosphatase and the target of immunosuppressants, is a critical regulator of Ca 2+ signaling. To discover novel CN‐regulated processes, we examined an understudied isoform, CNAb1, that is highly conserved across vertebrates and expressed in every human tissue. CN is a heterodimer of regulatory and catalytic subunits whose functions and regulation by Ca 2+ and calmodulin are well understood for canonical CN isozymes. The few studies of CNAb1, demonstrate its unique physiological and biochemical properties, however, mechanisms that confer these properties and CNAb1‐ specific substrates remain unknown. Here, we show that the non‐canonical C‐terminus of CNAb1, generated by alternative 3’ pre‐mRNA processing, confers unique intracellular localization, enzymatic regulation and substrate specificity for this isoform. In vitro, CNAb1 displays distinct enzymatic properties, where instead of the auto‐inhibitory domain that blocks the active site of canonical CN isoforms under non‐signaling conditions, CNAβ1 is autoinhibited by a sequence motif at its C tail that blocks substrate binding. In cells, unlike canonical cytosolic CN, CNAb1 localizes to the plasma membrane and Golgi due to palmitoylation of its divergent C‐terminal tail. This palmitoylation, which is dynamically regulated by the ABHD17A depalmitoylase, targets CNAb1 to distinct set of membrane‐associated interactors including the phosphatidylinositol 4‐kinase (PI4KA) complex containing EFR3B, PI4KA, TTC7B and FAM126A. This complex recruits the cytosolic PI4KIIIA to the PM where it synthesizes phosphatidylinositol‐4‐phosphate (PI4P), a precursor of the critical signaling phospholipid, PI(4,5)P 2 , required for sustained Ca 2+ signaling through GPCRs. Using hydrogen‐deuterium exchange, we reveal multiple CN‐PI4KA complex contacts, including a calcineurin‐binding peptide motif in the disordered tail of FAM126A which we further establish as a novel calcineurin substrate. Using BRET‐based detection of phosphoinositides in live cells, we show that CN inhibitors decrease PM PI4P production during Gq‐coupled muscarinic receptor signaling, suggesting that CN dephosphorylates and promotes PI4KA complex activity. Together, this work not only discovers dynamic palmitoylation as a novel mechanism that confers unique localization, substrate specificity and regulation to CNAb1 but also uncovers a novel Ca 2+ /CN‐mediated, feedback loop, that promotes PI4P replenishment at the PM during GPCR signaling.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".