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

Area of Science:

• Biochemistry
• Cell Biology
• Toxicology

Background:

• Methylselenol (MeSeH) is a cytotoxic selenium metabolite implicated in cancer cell apoptosis.
• Previous studies in yeast identified O-acetylhomoserine (OAH)-sulfhydrylase as key in MeSeH toxicity, an enzyme absent in higher eukaryotes.
• Understanding alternative MeSeH targets is crucial for elucidating its mechanisms in various organisms.

Purpose of the Study:

• To identify alternative targets and mechanisms of Methylselenol (MeSeH) toxicity in yeast lacking O-acetylhomoserine (OAH)-sulfhydrylase.
• To investigate the role of endoplasmic reticulum (ER) stress and oxidative stress responses in MeSeH-induced cytotoxicity.
• To elucidate the impact of MeSeH on protein folding and redox homeostasis within the ER.

Main Methods:

• Utilized a met17 mutant yeast strain deficient in OAH-sulfhydrylase activity.
• Assessed cellular responses to dimethyldiselenide (DMDSe), a MeSeH precursor, including gene expression and protein maturation.
• Examined the sensitivity of various mutant strains (∆ire1, ∆hac1, ∆YAP1, ∆SKN7) to DMDSe and selenomethionine.

Main Results:

• Exposure to DMDSe induced endoplasmic reticulum (ER) stress, evidenced by increased Kar2p expression.
• Mutant strains deficient in the unfolded protein response (∆ire1, ∆hac1) were hypersensitive to MeSeH precursors.
• Impaired ER maturation of carboxypeptidase Y and altered Ero1p redox status indicated protein misfolding and reductive stress in the ER.

Conclusions:

• MeSeH and its precursor DMDSe induce ER stress and protein misfolding in yeast.
• The toxicity is mediated through the unfolded protein response pathway, not oxidative stress response pathways.
• MeSeH perturbs protein folding in the ER by inducing a reductive stress environment.