Calcium-independent phospholipase A2γ enhances activation of the ATF6 transcription factor during endoplasmic reticulum stress.
Injury of visceral glomerular epithelial cells (GECs) causes proteinuria in many glomerular diseases. We reported previously that calcium-independent phospholipase A2γ (iPLA2γ) is cytoprotective against complement-mediated GEC injury. Because iPLA2γ is localized at the endoplasmic reticulum (ER), this study addressed whether the cytoprotective effect of iPLA2γ involves the ER stress unfolded protein response (UPR). In cultured rat GECs, overexpression of the full-length iPLA2γ, but not a mutant iPLA2γ 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 iPLA2γ inhibitor, (R)-bromoenol lactone, but not by the cyclooxygenase inhibitor, indomethacin. Tunicamycin-induced cytotoxicity was reduced in GECs expressing iPLA2γ, and the cytoprotection was reversed by dominant-negative ATF6. GECs from iPLA2γ 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 iPLA2γ. Thus, in GECs, iPLA2γ amplified activation of the ATF6 pathway of the UPR, resulting in up-regulation of ER chaperones and cytoprotection. These effects were dependent on iPLA2γ catalytic activity and association with the ER but not on prostanoids. Modulating iPLA2γ activity may provide opportunities for pharmacological intervention in glomerular diseases associated with ER stress.
['Elimam|Hanan|H|', 'Papillon|Joan|J|', 'Takano|Tomoko|T|', 'Cybulsky|Andrey V|AV|']
D051702:Activating Transcription Factor 6 D000818:Animals D019556:COS Cells D002522:Chlorocebus aethiops D000091342:Endoplasmic Reticulum Chaperone BiP D059865:Endoplasmic Reticulum Stress D051379:Mice D018345:Mice, Knockout D008856:Microscopy, Fluorescence D054512:Phospholipases A2, Calcium-Independent D051381:Rats D020133:Reverse Transcriptase Polymerase Chain Reaction D014415:Tunicamycin
Endoplasmic Reticulum (ER) Unfolded Protein Response (UPR) Cell Death Cell Signaling Endoplasmic Reticulum Stress (ER Stress) Phospholipase A