Hiraoka Hideki, Nakahara Kengo, Kaneko Yuki, Akiyama Shiori, Okuda Kosaku, Iwawaki Takao, Fujimura Masatake, Kumagai Yoshito, Takasugi Nobumasa, Uehara Takashi
Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University.
Division of Cell Medicine, Department of Life Science, Medical Research Institute, Kanazawa Medical University.
Biol Pharm Bull. 2017;40(9):1595-1598. doi: 10.1248/bpb.b17-00359.
Methylmercury (MeHg) results in cell death through endoplasmic reticulum (ER) stress. Previously, we reported that MeHg induces S-mercuration at cysteine 383 or 386 in protein disulfide isomerase (PDI), and this modification induces the loss of enzymatic activity. Because PDI is a key enzyme for the maturation of nascent protein harboring a disulfide bond, the disruption in PDI function by MeHg results in ER stress via the accumulation of misfolded proteins. However, the effects of MeHg on unfolded protein response (UPR) sensors and their signaling remain unclear. In the present study, we show that UPR is regulated by MeHg. We found that MeHg specifically attenuated inositol-requiring enzyme 1α (IRE1α)-x-box binding protein 1 (XBP1) branch, but not the protein kinase RNA-like endoplasmic reticulum kinase (PERK) and activating transcriptional factor 6 (ATF6) branches. Treatment with GSK2606414, a specific PERK inhibitor, significantly inhibited MeHg-induced cell death. These findings suggest that MeHg exquisitely regulates UPR signaling involved in cell death.
甲基汞（MeHg）通过内质网（ER）应激导致细胞死亡。此前，我们报道MeHg会在蛋白质二硫键异构酶（PDI）的半胱氨酸383或386处诱导S-汞化，这种修饰会导致酶活性丧失。由于PDI是具有二硫键的新生蛋白质成熟的关键酶，MeHg对PDI功能的破坏会通过错误折叠蛋白质的积累导致内质网应激。然而，MeHg对未折叠蛋白反应（UPR）传感器及其信号传导的影响仍不清楚。在本研究中，我们表明UPR受MeHg调节。我们发现MeHg特异性减弱了肌醇需求酶1α（IRE1α）-X盒结合蛋白1（XBP1）分支，但不影响蛋白激酶RNA样内质网激酶（PERK）和激活转录因子6（ATF6）分支。用特异性PERK抑制剂GSK2606414处理可显著抑制MeHg诱导的细胞死亡。这些发现表明MeHg精确调节参与细胞死亡的UPR信号传导。
