TY - JOUR
T1 - Modulation of unfolded protein response by methylmercury
AU - Hiraoka, Hideki
AU - Nakahara, Kengo
AU - Kaneko, Yuki
AU - Akiyama, Shiori
AU - Okuda, Kosaku
AU - Iwawaki, Takao
AU - Fujimur, Masatake
AU - Kumagai, Yoshito
AU - Takasugi, Nobumasa
AU - Uehara, Takashi
N1 - Funding Information:
Acknowledgments We thank Ms. Yoko Okamoto for providing technical assistance. The Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan Grants-in-Aid for Scientific Research (B) 15H04649, Challenging Exploratory Research 15K14952; The Shimabara Science Promotion Foundation; and the Smoking Research Foundation supported this study.
Publisher Copyright:
© 2017 The Pharmaceutical Society of Japan.
PY - 2017
Y1 - 2017
N2 - 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.
AB - 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.
KW - Endoplasmic reticulum (ER) stress
KW - Methylmercury
KW - Unfolded protein response; cell death
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U2 - 10.1248/bpb.b17-00359
DO - 10.1248/bpb.b17-00359
M3 - Article
C2 - 28867746
AN - SCOPUS:85029445065
SN - 0918-6158
VL - 40
SP - 1595
EP - 1598
JO - Biological and Pharmaceutical Bulletin
JF - Biological and Pharmaceutical Bulletin
IS - 9
ER -