title: Calcium-independent phospholipase A2γ enhances activation of the ATF6 transcription factor during endoplasmic reticulum stress.
abstract: 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.
authors.affiliation: From the Department of Medicine, McGill University Health Centre, McGill University, Montreal, Quebec H3A 1A1, Canada.
authors.forename: Hanan
authors.initials: H
authors.lastname: Elimam
authors.affiliation: From the Department of Medicine, McGill University Health Centre, McGill University, Montreal, Quebec H3A 1A1, Canada.
authors.forename: Joan
authors.initials: J
authors.lastname: Papillon
authors.affiliation: From the Department of Medicine, McGill University Health Centre, McGill University, Montreal, Quebec H3A 1A1, Canada tomoko.takano@mcgill.ca.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Takano
authors.affiliation: From the Department of Medicine, McGill University Health Centre, McGill University, Montreal, Quebec H3A 1A1, Canada andrey.cybulsky@mcgill.ca.
authors.forename: Andrey V
authors.initials: AV
authors.lastname: Cybulsky
mesh_terms: D051702:Activating Transcription Factor 6 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D054512:Phospholipases A2, Calcium-Independent / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014415:Tunicamycin / Q000494:pharmacology
chemical_list: D051702:Activating Transcription Factor 6; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717248:Hspa5 protein, mouse; D014415:Tunicamycin; D054512:Phospholipases A2, Calcium-Independent
keywords: Cell Death; Cell Signaling; Endoplasmic Reticulum (ER); Endoplasmic Reticulum Stress (ER Stress); Phospholipase A; Unfolded Protein Response (UPR)