Correlation Between Attenuation of Protein Disulfide Isomerase Activity Through S-Mercuration and Neurotoxicity Induced by Methylmercury

Makino, Kento; Okuda, Kosaku; Sugino, Eisuke; Nishiya, Tadashi; Toyama, Takashi; Fujimura, Masatake; Kumagai, Yoshito; Uehara, Takashi

doi:10.1007/s12640-014-9494-8

Cited by 26 publications

(15 citation statements)

References 31 publications

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“…A subsequent study showed that pretreatment with Trolox significantly blocked MeHg-induced ER stress, unfolded protein response activation, and apoptosis in neuronal cells [ 71 ], confirming that MeHg-mediated oxidative stress causes ER stress and apoptosis. In contrast, it has been reported that MeHg directly causes ER stress through interaction with protein disulfide isomerase (PDI) [ 18 ]. PDI localizes in the ER and catalyzes all of the reactions involved in native disulfide bond formation in the ER [ 82 ].…”

Section: Cellular Stress Pathways Triggered By Mehg-mediated Oxidamentioning

confidence: 99%

“…It has been demonstrated that the dysfunction of PDI enzymatic activity by the oxidative modification of active cysteine by nitric oxide (NO) induced by treatment with N-Methyl-D-aspartate causes the accumulation of newly synthesized unfolded protein in the ER lumen, resulting ER stress [ 86 ]. Similar to NO, the MeHg-modified C-terminal catalytic domain in PDI was detected using matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF/MS) analysis, suggesting that PDI is a target protein for MeHg in the ER [ 18 ]. In addition, treatment with MeHg significantly attenuated the enzymatic activity of PDI.…”

Section: Cellular Stress Pathways Triggered By Mehg-mediated Oxidamentioning

confidence: 99%

“…It has been revealed that high affinity for selenohydryl groups, sulfhydryl groups, and selenides [ 15 ] plays a critical role in the incidence of MeHg toxicity [ 16 , 17 , 18 ]. Many antioxidant enzymes and proteins have thiol and selenol residues.…”

Section: Introductionmentioning

confidence: 99%

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Methylmercury-Mediated Oxidative Stress and Activation of the Cellular Protective System

Fujimura

Usuki

2020

Antioxidants

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Methylmercury (MeHg) is a well-known neurotoxicant that causes severe intoxication in humans. In Japan, it is referred to as Minamata disease, which involves two characteristic clinical forms: fetal type and adult type depending on the exposed age. In addition to MeHg burden level, individual susceptibility to MeHg plays a role in the manifestation of MeHg toxicity. Research progress has pointed out the importance of oxidative stress in the pathogenesis of MeHg toxicity. MeHg has a high affinity for selenohydryl groups, sulfhydryl groups, and selenides. It has been clarified that such affinity characteristics cause the impairment of antioxidant enzymes and proteins, resulting in the disruption of antioxidant systems. Furthermore, MeHg-induced intracellular selenium deficiency due to the greater affinity of MeHg for selenohydryl groups and selenides leads to failure in the recoding of a UGA codon for selenocysteine and results in the degradation of antioxidant selenoenzyme mRNA by nonsense-mediated mRNA decay. The defect of antioxidant selenoenzyme replenishment exacerbates MeHg-mediated oxidative stress. On the other hand, it has also been revealed that MeHg can directly activate the antioxidant Keap1/Nrf2 signaling pathway. This review summarizes the incidence of MeHg-mediated oxidative stress from the viewpoint of the individual intracellular redox system interactions and the MeHg-mediated aforementioned intracellular events. In addition, the mechanisms of cellular stress pathways and neuronal cell death triggered by MeHg-mediated oxidative stress and direct interactions of MeHg with reactive residues of proteins are mentioned.

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Section: Cellular Stress Pathways Triggered By Mehg-mediated Oxidamentioning

confidence: 99%

Section: Cellular Stress Pathways Triggered By Mehg-mediated Oxidamentioning

confidence: 99%

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Methylmercury-Mediated Oxidative Stress and Activation of the Cellular Protective System

Fujimura

Usuki

2020

Antioxidants

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“…Like the two active TrpCysGly-HisCysLys sites of PDI, Cys residues that are adjacent to a basic environment (i.e., Lys, Arg, or His) have low pKa values and are targeted for covalent modification. In the ER, S-nitrosylation, S-glutathionylation, and S-mercuration occur on the active sites of PDI, inhibiting its enzymatic activity and promoting the unfolded protein response and ER stress 15,52,53 . Uehara et al reported that PDI is S-nitrosylated in brain tissues from patients with Parkinson's and Alzheimer's diseases and that S-nitrosylation impairs the protective effect of PDI on neurotoxicity that is induced by protein misfolding in neurodegenerative disorders 15 .…”

Section: Regulators Of Extracellular Pdi Activitymentioning

confidence: 99%

Protein disulfide isomerase in cardiovascular disease

et al. 2020

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Protein disulfide isomerase (PDI) participates in the pathogenesis of numerous diseases. Increasing evidence indicates that intravascular cell-derived PDI plays an important role in the initiation and progression of cardiovascular diseases, including thrombosis and vascular inflammation. Recent studies with PDI conditional knockout mice have advanced our understanding of the function of cell-specific PDI in disease processes. Furthermore, the identification and development of novel small-molecule PDI inhibitors has led into a new era of PDI research that transitioned from the bench to bedside. In this review, we will discuss recent findings on the regulatory role of PDI in cardiovascular disease.

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“…7,8) S-Nitrosylation and -mercuration of PDI in active sites promote endoplasmic reticulum (ER) stress and unfolded protein response (UPR). We earlier demonstrated that inositol-requiring enzyme 1α (IRE1α), a sensor of ER stress that is located within the ER membrane, is also directly modified and regulated by NO.…”

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confidence: 99%

Modulation of Unfolded Protein Response by Methylmercury

Hiraoka

Nakahara

Kaneko

et al. 2017

Biological & Pharmaceutical Bulletin

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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.

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Correlation Between Attenuation of Protein Disulfide Isomerase Activity Through S-Mercuration and Neurotoxicity Induced by Methylmercury

Cited by 26 publications

References 31 publications

Methylmercury-Mediated Oxidative Stress and Activation of the Cellular Protective System

Methylmercury-Mediated Oxidative Stress and Activation of the Cellular Protective System

Protein disulfide isomerase in cardiovascular disease

Modulation of Unfolded Protein Response by Methylmercury

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