Exposure to the Methylselenol Precursor Dimethyldiselenide Induces a Reductive Endoplasmic Reticulum Stress in <i>Saccharomyces cerevisiae</i>
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 <i>Saccharomyces cerevisiae</i>, MeSeH toxicity was mediated by its metabolization into seleno...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-05-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/22/11/5467 |
| _version_ | 1797533102703116288 |
|---|---|
| author | Marc Dauplais Pierre Mahou Pierre Plateau Myriam Lazard |
| author_facet | Marc Dauplais Pierre Mahou Pierre Plateau Myriam Lazard |
| author_sort | Marc Dauplais |
| collection | DOAJ |
| description | 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 <i>Saccharomyces cerevisiae</i>, 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 <i>met17</i> 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 (∆<i>ire1</i> and ∆<i>hac1</i>) unable to activate the unfolded protein response were hypersensitive to MeSeH precursors but not to selenomethionine. In contrast, deletion of <i>YAP1</i> or <i>SKN7</i>, 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. |
| first_indexed | 2024-03-10T11:09:48Z |
| format | Article |
| id | doaj.art-e9f8cee2176d4774a34b50ce70d00a89 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T11:09:48Z |
| publishDate | 2021-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-e9f8cee2176d4774a34b50ce70d00a892023-11-21T20:54:32ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-05-012211546710.3390/ijms22115467Exposure to the Methylselenol Precursor Dimethyldiselenide Induces a Reductive Endoplasmic Reticulum Stress in <i>Saccharomyces cerevisiae</i>Marc Dauplais0Pierre Mahou1Pierre Plateau2Myriam Lazard3Laboratoire de Biologie Structurale de la Cellule, BIOC, École Polytechnique, CNRS-UMR7654, IP Paris, 91128 Palaiseau, FranceLaboratoire d’Optique et Biosciences, École Polytechnique, CNRS UMR7645—INSERM U1182, IP Paris, 91128 Palaiseau, FranceLaboratoire de Biologie Structurale de la Cellule, BIOC, École Polytechnique, CNRS-UMR7654, IP Paris, 91128 Palaiseau, FranceLaboratoire de Biologie Structurale de la Cellule, BIOC, École Polytechnique, CNRS-UMR7654, IP Paris, 91128 Palaiseau, FranceMethylselenol (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 <i>Saccharomyces cerevisiae</i>, 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 <i>met17</i> 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 (∆<i>ire1</i> and ∆<i>hac1</i>) unable to activate the unfolded protein response were hypersensitive to MeSeH precursors but not to selenomethionine. In contrast, deletion of <i>YAP1</i> or <i>SKN7</i>, 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.https://www.mdpi.com/1422-0067/22/11/5467seleniummethylselenoldimethyldiselenideER stressreductive stressunfolded protein response |
| spellingShingle | Marc Dauplais Pierre Mahou Pierre Plateau Myriam Lazard Exposure to the Methylselenol Precursor Dimethyldiselenide Induces a Reductive Endoplasmic Reticulum Stress in <i>Saccharomyces cerevisiae</i> International Journal of Molecular Sciences selenium methylselenol dimethyldiselenide ER stress reductive stress unfolded protein response |
| title | Exposure to the Methylselenol Precursor Dimethyldiselenide Induces a Reductive Endoplasmic Reticulum Stress in <i>Saccharomyces cerevisiae</i> |
| title_full | Exposure to the Methylselenol Precursor Dimethyldiselenide Induces a Reductive Endoplasmic Reticulum Stress in <i>Saccharomyces cerevisiae</i> |
| title_fullStr | Exposure to the Methylselenol Precursor Dimethyldiselenide Induces a Reductive Endoplasmic Reticulum Stress in <i>Saccharomyces cerevisiae</i> |
| title_full_unstemmed | Exposure to the Methylselenol Precursor Dimethyldiselenide Induces a Reductive Endoplasmic Reticulum Stress in <i>Saccharomyces cerevisiae</i> |
| title_short | Exposure to the Methylselenol Precursor Dimethyldiselenide Induces a Reductive Endoplasmic Reticulum Stress in <i>Saccharomyces cerevisiae</i> |
| title_sort | exposure to the methylselenol precursor dimethyldiselenide induces a reductive endoplasmic reticulum stress in i saccharomyces cerevisiae i |
| topic | selenium methylselenol dimethyldiselenide ER stress reductive stress unfolded protein response |
| url | https://www.mdpi.com/1422-0067/22/11/5467 |
| work_keys_str_mv | AT marcdauplais exposuretothemethylselenolprecursordimethyldiselenideinducesareductiveendoplasmicreticulumstressinisaccharomycescerevisiaei AT pierremahou exposuretothemethylselenolprecursordimethyldiselenideinducesareductiveendoplasmicreticulumstressinisaccharomycescerevisiaei AT pierreplateau exposuretothemethylselenolprecursordimethyldiselenideinducesareductiveendoplasmicreticulumstressinisaccharomycescerevisiaei AT myriamlazard exposuretothemethylselenolprecursordimethyldiselenideinducesareductiveendoplasmicreticulumstressinisaccharomycescerevisiaei |