Kranz Philip, Neumann Fabian, Wolf Alexandra, Classen Fabian, Pompsch Mosche, Ocklenburg Tobias, Baumann Jennifer, Janke Kirsten, Baumann Melanie, Goepelt Kirsten, Riffkin Helena, Metzen Eric, Brockmeier Ulf
Institut für Physiologie, Universität Duisburg-Essen, Hufelandstraße 55, D45122 Essen, Germany.
Cell Death Dis. 2017 Aug 10;8(8):e2986. doi: 10.1038/cddis.2017.369.
Endoplasmic reticulum (ER) stress leads to activation of the unfolded protein response (UPR) that results in transient suppression of protein translation to allow recovery but leads to cell death when stress cannot be resolved. Central to initiation of the UPR is the activation of the ER transmembrane kinase protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK). Here we report that the thiol oxidoreductase ERp57 and protein disulfide isomerase-A1 (PDI), which belong to the same family of luminal ER oxidoreductases, have strikingly opposing roles in the regulation of PERK function. In HCT116 colon carcinoma cells, lentiviral depletion of ERp57 resulted in oxidation of PDI and activation of PERK, whereas depletion or chemical inhibition of PDI reduced PERK signaling and sensitized the cancer cells to hypoxia and ER stress. We conclude that oxidized PDI acts as a PERK activator, whereas ERp57 keeps PDI in a reduced state in the absence of ER stress. Thus, our study defines a new interface between metabolic redox signaling and PERK-dependent activation of the UPR and has the potential to influence future cancer therapies that target PERK signaling.
内质网（ER）应激会导致未折叠蛋白反应（UPR）的激活，这会暂时抑制蛋白质翻译以促进恢复，但当应激无法解决时会导致细胞死亡。UPR启动的核心是内质网跨膜激酶蛋白激酶R（PKR）样内质网激酶（PERK）的激活。在此，我们报告硫醇氧化还原酶ERp57和蛋白二硫键异构酶-A1（PDI），它们属于内质网腔氧化还原酶的同一家族，在PERK功能的调节中具有显著相反的作用。在HCT116结肠癌细胞中，ERp57的慢病毒介导的缺失导致PDI氧化和PERK激活，而PDI的缺失或化学抑制则降低了PERK信号传导，并使癌细胞对缺氧和内质网应激敏感。我们得出结论，氧化型PDI作为PERK激活剂，而在没有内质网应激的情况下，ERp57使PDI保持还原状态。因此，我们的研究定义了代谢氧化还原信号与UPR的PERK依赖性激活之间的新界面，并有可能影响未来针对PERK信号传导的癌症治疗。
