Calcium-independent Phospholipase A2γ Enhances Activation of the ATF6 Transcription Factor during Endoplasmic Reticulum Stress
Bibliographic record
Abstract
Injury of visceral glomerular epithelial cells (GECs) causes proteinuria in many glomerular diseases. We reported previously that calcium-independent phospholipase A 2 γ (iPLA 2 γ) is cytoprotective against complement-mediated GEC injury. Because iPLA 2 γ is localized at the endoplasmic reticulum (ER), this study addressed whether the cytoprotective effect of iPLA 2 γ involves the ER stress unfolded protein response (UPR). In cultured rat GECs, overexpression of the full-length iPLA 2 γ, but not a mutant iPLA 2 γ that fails to associate with the ER, augmented tunicamycin-induced activation of activating transcription factor-6 (ATF6) and induction of the ER chaperones, glucose-regulated protein 94 (GRP94) and glucose-regulated protein 78 (GRP78). Augmented responses were inhibited by the iPLA 2 γ inhibitor, ( R )-bromoenol lactone, but not by the cyclooxygenase inhibitor, indomethacin. Tunicamycin-induced cytotoxicity was reduced in GECs expressing iPLA 2 γ, and the cytoprotection was reversed by dominant-negative ATF6. GECs from iPLA 2 γ knock-out mice showed blunted ATF6 activation and chaperone up-regulation in response to tunicamycin. Unlike ATF6, the two other UPR pathways, i.e. inositol-requiring enzyme 1α and protein kinase RNA-like ER kinase pathways, were not affected by iPLA 2 γ. Thus, in GECs, iPLA 2 γ amplified activation of the ATF6 pathway of the UPR, resulting in up-regulation of ER chaperones and cytoprotection. These effects were dependent on iPLA 2 γ catalytic activity and association with the ER but not on prostanoids. Modulating iPLA 2 γ activity may provide opportunities for pharmacological intervention in glomerular diseases associated with ER stress. Background: Calcium-independent PLA 2 γ (iPLA 2 γ) is a membrane-bound enzyme that localizes at the endoplasmic reticulum (ER). Results: iPLA 2 γ amplified activation of the ATF6 pathway of the unfolded protein response, resulting in up-regulation of ER chaperones and cytoprotection. Conclusion: iPLA 2 γ enhances activation of ATF6. Significance: Modulating iPLA 2 γ activity may provide opportunities for pharmacological intervention in glomerular diseases associated with ER stress.
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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".