Calcium-independent Phospholipase A2{gamma} Enhances Activation of the ATF6 Transcription Factor During Endoplasmic Reticulum Stress [Signal Transduction]

December 9th, 2014 by Elimam, H., Papillon, J., Takano, T., Cybulsky, A. V.

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. Since iPLA2γ is localized at the endoplasmic reticulum (ER), the present 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 grp78. Augmented responses were inhibited by the iPLA2γ inhibitor, R-bromoenol lactone (R-BEL), 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 knockout mice showed blunted ATF6 activation and chaperone upregulation in response to tunicamycin. Unlike ATF6, the two other UPR pathways i.e. inositol-requiring 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 upregulation 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.
  • Posted in Journal of Biological Chemistry, Publications
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