Calcium-independent Phospholipase A2γ Enhances Activation of the ATF6 Transcription Factor during Endoplasmic Reticulum Stress

Background: Calcium-independent PLA(2) (iPLA(2)) is a membrane-bound enzyme that localizes at the endoplasmic reticulum (ER). Results: iPLA(2) amplified activation of the ATF6 pathway of the unfolded protein response, resulting in up-regulation of ER chaperones and cytoprotection. Conclusion: iPLA(2) enhances activation of ATF6. Significance: Modulating iPLA(2) activity may provide opportunities for pharmacological intervention in glomerular diseases associated with ER stress. Injury of visceral glomerular epithelial cells (GECs) causes proteinuria in many glomerular diseases. We reported previously that calcium-independent phospholipase A(2) (iPLA(2)) is cytoprotective against complement-mediated GEC injury. Because iPLA(2) is localized at the endoplasmic reticulum (ER), this study addressed whether the cytoprotective effect of iPLA(2) involves the ER stress unfolded protein response (UPR). In cultured rat GECs, overexpression of the full-length iPLA(2), but not a mutant iPLA(2) 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) inhibitor, (R)-bromoenol lactone, but not by the cyclooxygenase inhibitor, indomethacin. Tunicamycin-induced cytotoxicity was reduced in GECs expressing iPLA(2), and the cytoprotection was reversed by dominant-negative ATF6. GECs from iPLA(2) 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 1 and protein kinase RNA-like ER kinase pathways, were not affected by iPLA(2). Thus, in GECs, iPLA(2) 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) catalytic activity and association with the ER but not on prostanoids. Modulating iPLA(2) activity may provide opportunities for pharmacological intervention in glomerular diseases associated with ER stress.