| First Author | Elimam H | Year | 2015 |
| Journal | J Biol Chem | Volume | 290 |
| Issue | 5 | Pages | 3009-20 |
| PubMed ID | 25492867 | Mgi Jnum | J:219357 |
| Mgi Id | MGI:5620555 | Doi | 10.1074/jbc.M114.592261 |
| Citation | Elimam H, et al. (2015) Calcium-independent phospholipase A2gamma enhances activation of the ATF6 transcription factor during endoplasmic reticulum stress. J Biol Chem 290(5):3009-20 |
| abstractText | Injury of visceral glomerular epithelial cells (GECs) causes proteinuria in many glomerular diseases. We reported previously that calcium-independent phospholipase A2gamma (iPLA2gamma) is cytoprotective against complement-mediated GEC injury. Because iPLA2gamma is localized at the endoplasmic reticulum (ER), this study addressed whether the cytoprotective effect of iPLA2gamma involves the ER stress unfolded protein response (UPR). In cultured rat GECs, overexpression of the full-length iPLA2gamma, but not a mutant iPLA2gamma 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 iPLA2gamma inhibitor, (R)-bromoenol lactone, but not by the cyclooxygenase inhibitor, indomethacin. Tunicamycin-induced cytotoxicity was reduced in GECs expressing iPLA2gamma, and the cytoprotection was reversed by dominant-negative ATF6. GECs from iPLA2gamma 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 1alpha and protein kinase RNA-like ER kinase pathways, were not affected by iPLA2gamma. Thus, in GECs, iPLA2gamma amplified activation of the ATF6 pathway of the UPR, resulting in up-regulation of ER chaperones and cytoprotection. These effects were dependent on iPLA2gamma catalytic activity and association with the ER but not on prostanoids. Modulating iPLA2gamma activity may provide opportunities for pharmacological intervention in glomerular diseases associated with ER stress. |
