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Exposure to the Methylselenol Precursor Dimethyldiselenide Induces a Reductive Endoplasmic Reticulum Stress in Saccharomyces cerevisiae

Authors :
Pierre Plateau
Marc Dauplais
Myriam Lazard
Pierre Mahou
Laboratoire de Biochimie de l'Ecole polytechnique (BIOC)
École polytechnique (X)-Centre National de la Recherche Scientifique (CNRS)
Laboratoire d'Optique et Biosciences (LOB)
Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École polytechnique (X)
Laboratoire de Biologie Structurale de la Cellule (BIOC)
École polytechnique (X)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Lazard, Myriam
Source :
International Journal of Molecular Sciences, Volume 22, Issue 11, International Journal of Molecular Sciences, MDPI, 2021, 22 (11), pp.5467. ⟨10.3390/ijms22115467⟩, International Journal of Molecular Sciences, Vol 22, Iss 5467, p 5467 (2021), International Journal of Molecular Sciences, 2021, 22 (11), pp.5467. ⟨10.3390/ijms22115467⟩
Publication Year :
2021
Publisher :
Multidisciplinary Digital Publishing Institute, 2021.

Abstract

Methylselenol (MeSeH) is a major cytotoxic metabolite of selenium, causing apoptosis in cancer cells through mechanisms that remain to be fully established. Previously, we demonstrated that, in Saccharomyces cerevisiae, MeSeH toxicity was mediated by its metabolization into selenomethionine by O-acetylhomoserine (OAH)-sulfhydrylase, an enzyme that is absent in higher eukaryotes. In this report, we used a mutant met17 yeast strain, devoid of OAH- sulfhydrylase activity, to identify alternative targets of MeSeH. Exposure to dimethyldiselenide (DMDSe), a direct precursor of MeSeH, caused an endoplasmic reticulum (ER) stress, as evidenced by increased expression of the ER chaperone Kar2p. Mutant strains (∆ire1 and ∆hac1) unable to activate the unfolded protein response were hypersensitive to MeSeH precursors but not to selenomethionine. In contrast, deletion of YAP1 or SKN7, required to activate the oxidative stress response, did not affect cell growth in the presence of DMDSe. ER maturation of newly synthesized carboxypeptidase Y was impaired, indicating that MeSeH/DMDSe caused protein misfolding in the ER. Exposure to DMDSe resulted in induction of the expression of the ER oxidoreductase Ero1p with concomitant reduction of its regulatory disulfide bonds. These results suggest that MeSeH disturbs protein folding in the ER by generating a reductive stress in this compartment.

Details

Language :
English
ISSN :
14220067 and 16616596
Database :
OpenAIRE
Journal :
International Journal of Molecular Sciences
Accession number :
edsair.doi.dedup.....ce7de5ae8903881bd4b310d4594bd3ba
Full Text :
https://doi.org/10.3390/ijms22115467