title: Correlation between attenuation of protein disulfide isomerase activity through S-mercuration and neurotoxicity induced by methylmercury.
abstract: Methylmercury (MeHg), an environmental pollutant, causes neuronal death via endoplasmic reticulum (ER) stress; however, the precise mechanism is not fully understood. The aim of this study was to elucidate the possible mechanism of MeHg-induced neurotoxicity. Treatment with MeHg resulted in a loss of cell viability in a concentration-dependent manner accompanying the expression of ER stress marker genes in human neuroblastoma SH-SY5Y cells. We next attempted to identify a target protein for MeHg in the ER. MeHg covalently modified protein disulfide isomerase (PDI), which is important for disulfide bond formation in nascent proteins in the ER lumen. S-Nitrosylation of the catalytic domains of PDI by nitric oxide was attenuated up to 50 % by a MeHg challenge in cells. The MeHg-modified C-terminal catalytic domain in PDI was detected by MALDI-TOF/MS. Furthermore, treatment with MeHg significantly attenuated the enzymatic activity of PDI. Taken together, these observations suggest that MeHg results in ER stress and following the unfolded protein response pathway via ER dysfunction due to S-mercuration of the C-terminus of PDI.
authors.affiliation: Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
authors.forename: Kento
authors.initials: K
authors.lastname: Makino
authors.forename: Kosaku
authors.initials: K
authors.lastname: Okuda
authors.forename: Eisuke
authors.initials: E
authors.lastname: Sugino
authors.forename: Tadashi
authors.initials: T
authors.lastname: Nishiya
authors.forename: Takashi
authors.initials: T
authors.lastname: Toyama
authors.forename: Takao
authors.initials: T
authors.lastname: Iwawaki
authors.forename: Masatake
authors.initials: M
authors.lastname: Fujimura
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Kumagai
authors.forename: Takashi
authors.initials: T
authors.lastname: Uehara
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008767:Methylmercury Compounds / Q000633:toxicity*; D009842:Oligopeptides / Q000378:metabolism; D019704:Protein Disulfide-Isomerases / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051742:Transcription Factor CHOP / Q000378:metabolism
chemical_list: C539791:Bax-inhibiting peptide, BIP; C497249:DDIT3 protein, human; D008767:Methylmercury Compounds; D009842:Oligopeptides; D012333:RNA, Messenger; D051742:Transcription Factor CHOP; D019704:Protein Disulfide-Isomerases