Mihailidou Chrysovalantou, Panagiotou Christina, Kiaris Hippokratis, Kassi Eva, Moutsatsou Paraskevi
Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece; Department of Clinical Biochemistry, University Hospital "ATTIKO", Medical School, National and Kapodistrian University of Athens, Greece.
Mol Cell Endocrinol. 2016 Nov 15;436:211-23. doi: 10.1016/j.mce.2016.08.001. Epub 2016 Aug 3.
Loss of homeostasis triggers the endoplasmic reticulum (ER) stress response and activates the unfolded protein response (UPR) resulting in the induction of the CCAAT/enhancer binding protein (C/EBP) homologous protein (CHOP). Glucocorticoids (GCs), via the glucocorticoid receptor (GR), regulate numerous physiological processes in an effort to maintain homeostasis. Previous studies demonstrated that glucocorticoids suppress ER stress by enhancing correct folding of secreted proteins and degradation of misfolded proteins. Here, we describe a novel crosstalk between ER-stress and the glucocorticoid receptor signaling. We showed that treatment of wild type mice with Tunicamycin (inducer of ER-stress) increased GR protein levels in the lungs. Treatment of A549 cells (human lung cancer cells) with ER stress inducers modulated the Dexamethasone-induced subcellular localization of GR and the phosphorylated forms of GR (pGRSer211 and pGRSer203) with concomitant changes in the expression of primary GR-target genes. We demonstrated a significant protein-protein interaction between GR and CHOP, (GR-CHOP heterocomplex formation) under ER stress conditions. The functional consequences of ER stress- GR signaling crosstalk were assessed and demonstrated that long time exposure (24-48 h) of A549 cells to dexamethasone (10(-6) M) reversed the Tunicamycin-induced cell death, a phenomenon associated with parallel increases in GR protein content, increases in cell survival parameters and decreases in cell apoptosis-related parameters. Our study provides evidence that there is a cross talk between ER-stress and GR signaling, this being associated with mutual functional antagonism between CHOP and GR-mediated pathways in lung cells with important implications in lung cell function.
内环境稳态的丧失会触发内质网（ER）应激反应并激活未折叠蛋白反应（UPR），从而导致CCAAT/增强子结合蛋白（C/EBP）同源蛋白（CHOP）的诱导。糖皮质激素（GCs）通过糖皮质激素受体（GR）调节众多生理过程以维持内环境稳态。先前的研究表明，糖皮质激素通过增强分泌蛋白的正确折叠和错误折叠蛋白的降解来抑制内质网应激。在此，我们描述了内质网应激与糖皮质激素受体信号传导之间一种新的相互作用。我们发现用衣霉素（内质网应激诱导剂）处理野生型小鼠会增加肺中GR蛋白水平。用内质网应激诱导剂处理A549细胞（人肺癌细胞）可调节地塞米松诱导的GR亚细胞定位以及GR的磷酸化形式（pGRSer211和pGRSer203），同时伴随主要GR靶基因表达的变化。我们证实在内质网应激条件下GR与CHOP之间存在显著的蛋白质 - 蛋白质相互作用（GR - CHOP异源复合物形成）。对内质网应激 - GR信号相互作用的功能后果进行了评估，结果表明A549细胞长时间（24 - 48小时）暴露于地塞米松（10^(-6) M）可逆转衣霉素诱导的细胞死亡，这一现象与GR蛋白含量平行增加、细胞存活参数增加以及细胞凋亡相关参数降低有关。我们的研究提供了证据表明内质网应激与GR信号传导之间存在相互作用，这与肺细胞中CHOP和GR介导的途径之间的相互功能拮抗有关，对肺细胞功能具有重要意义。
