Modulation of unfolded protein response by methylmercury

Hideki Hiraoka, Kengo Nakahara, Yuki Kaneko, Shiori Akiyama, Kosaku Okuda, Takao Iwawaki, Masatake Fujimur, Yoshito Kumagai, Nobumasa Takasugi, Takashi Uehara

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1595-1598
Number of pages4
JournalBiological and Pharmaceutical Bulletin
Volume40
Issue number9
DOIs
Publication statusPublished - 2017

Keywords

  • Endoplasmic reticulum (ER) stress
  • Methylmercury
  • Unfolded protein response; cell death

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

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  • Cite this

    Hiraoka, H., Nakahara, K., Kaneko, Y., Akiyama, S., Okuda, K., Iwawaki, T., Fujimur, M., Kumagai, Y., Takasugi, N., & Uehara, T. (2017). Modulation of unfolded protein response by methylmercury. Biological and Pharmaceutical Bulletin, 40(9), 1595-1598. https://doi.org/10.1248/bpb.b17-00359