Stuck between a ROS and a hard place: Analysis of the ubiquitin proteasome pathway in selenocysteine treated Brassica napus reveals different toxicities during selenium assimilation

Dimkovikj, Aleksandar; Fisher, Brian D.; Hutchison, Kim; Hoewyk, Doug Van

doi:10.1016/j.jplph.2015.04.003

Cited by 19 publications

(14 citation statements)

References 29 publications

(31 reference statements)

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“…Minimizing the misincorporation of SeCys by introduction of a SeCys methyltransferase gene has also been an effective strategy to increase Se tolerance in plants4849. In addition, the ubiquitin-proteasome pathway, which we observe here to be important for SeMet tolerance in S. cerevisiae (Table 1), was recently implicated in SeCys toxicity in the plant Brassica napus 50. In cultured human cells, an increase of protein-bound selenium and the induction of an ER stress response were observed upon selenocystine treatment51, leading the authors to suggest that replacement of cysteine by SeCys in polypeptides triggered an accumulation of misfolded proteins.…”

Section: Discussionmentioning

confidence: 64%

Exposure to selenomethionine causes selenocysteine misincorporation and protein aggregation in Saccharomyces cerevisiae

Plateau

Saveanu

Lestini

et al. 2017

Sci Rep

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Selenomethionine, a dietary supplement with beneficial health effects, becomes toxic if taken in excess. To gain insight into the mechanisms of action of selenomethionine, we screened a collection of ≈5900 Saccharomyces cerevisiae mutants for sensitivity or resistance to growth-limiting amounts of the compound. Genes involved in protein degradation and synthesis were enriched in the obtained datasets, suggesting that selenomethionine causes a proteotoxic stress. We demonstrate that selenomethionine induces an accumulation of protein aggregates by a mechanism that requires de novo protein synthesis. Reduction of translation rates was accompanied by a decrease of protein aggregation and of selenomethionine toxicity. Protein aggregation was supressed in a ∆cys3 mutant unable to synthetize selenocysteine, suggesting that aggregation results from the metabolization of selenomethionine to selenocysteine followed by translational incorporation in the place of cysteine. In support of this mechanism, we were able to detect random substitutions of cysteinyl residues by selenocysteine in a reporter protein. Our results reveal a novel mechanism of toxicity that may have implications in higher eukaryotes.

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Section: Discussionmentioning

confidence: 64%

Exposure to selenomethionine causes selenocysteine misincorporation and protein aggregation in Saccharomyces cerevisiae

Plateau

Saveanu

Lestini

et al. 2017

Sci Rep

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“…It is highly possible that in order to keep a similar protein content a higher turnover of non-specific selenoproteins is required in presence of Se. Support to this assumption also comes from recent work in different organisms including human cells (Wallenberg et al 2014), chlamydomonas (Vallentine et al 2014) and Brassica napus (Dimkovikj et al 2015) that in presence of Se display increased levels of ubiquitinated proteins as well as proteasome activity. Notably the construction of protein pools is much more energetically expensive as compared with carbohydrate biosynthesis (Pal et al 2013, Ishihara et al 2015.…”

Section: Discussionmentioning

confidence: 84%

“…) and Brassica napus (Dimkovikj et al . ) that in presence of Se display increased levels of ubiquitinated proteins as well as proteasome activity. Notably the construction of protein pools is much more energetically expensive as compared with carbohydrate biosynthesis (Pal et al .…”

Section: Discussionmentioning

confidence: 92%

Growth inhibition by selenium is associated with changes in primary metabolism and nutrient levels in Arabidopsis thaliana

Ribeiro

Júnior

Cardoso

et al. 2016

Plant Cell & Environment

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Although Selenium (Se) stress is relatively well known for causing growth inhibition, its effects on primary metabolism remain rather unclear. Here, we characterized both the modulation of the expression of specific genes and the metabolic adjustments in Arabidopsis thaliana in response to changes in Se level in the soil. Se treatment culminated with strong inhibition of both shoot and root growth. Notably, growth inhibition in Se-treated plants was associated with an incomplete mobilization of starch during the night. Minor changes in amino acids levels were observed in shoots and roots of plants treated with Se whereas the pool size of tricarboxylic acid (TCA) cycle intermediates in root was not altered in response to Se. By contrast, decreased levels of organic acids involved in the first part of the TCA cycle were observed in shoots of Se-treated plants. Furthermore, decreased expression levels of expansins and endotransglucosylases/endohydrolases (XHTs) genes were observed after Se treatment, coupled with a significant decrease in the levels of essential elements. Collectively, our results revealed an exquisite interaction between energy metabolism and Se-mediated control of growth in Arabidopsis thaliana to coordinate cell wall extension, starch turnover and the levels of a few essential nutrients.

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“…The same authors showed that SeCystine triggered endoplasmic reticulum (ER) stress, the unfolded protein response, an increase in protein ubiquitination and extensive cytoplasmic vacuolarization in HeLa cells, in the absence of DNA damage (120). In higher plants also, evidence was recently provided that SeCys treatment impairs protein homeostasis without elevation of superoxide levels (121,122). It was also reported that a mutation of Arabidopsis thaliana BiP2 protein, an ER chaperone that binds to misfolded proteins, prevented germination when plants were grown on SeCys, suggesting errors in ER protein folding or quality control (121).…”

Section: Selenocyst(e)ine Toxicitymentioning

confidence: 99%

Recent advances in the mechanism of selenoamino acids toxicity in eukaryotic cells

Lazard

Dauplais

Blanquet

et al. 2017

Biomolecular Concepts

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Selenium is an essential trace element due to its incorporation into selenoproteins with important biological functions. However, at high doses it is toxic. Selenium toxicity is generally attributed to the induction of oxidative stress. However, it has become apparent that the mode of action of seleno-compounds varies, depending on its chemical form and speciation. Recent studies in various eukaryotic systems, in particular the model organism Saccharomyces cerevisiae, provide new insights on the cytotoxic mechanisms of selenomethionine and selenocysteine. This review first summarizes current knowledge on reactive oxygen species (ROS)-induced genotoxicity of inorganic selenium species. Then, we discuss recent advances on our understanding of the molecular mechanisms of selenocysteine and selenomethionine cytotoxicity. We present evidences indicating that both oxidative stress and ROSindependent mechanisms contribute to selenoamino acids cytotoxicity. These latter mechanisms include disruption of protein homeostasis by selenocysteine misincorporation in proteins and/or reaction of selenols with protein thiols.

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Stuck between a ROS and a hard place: Analysis of the ubiquitin proteasome pathway in selenocysteine treated Brassica napus reveals different toxicities during selenium assimilation

Cited by 19 publications

References 29 publications

Exposure to selenomethionine causes selenocysteine misincorporation and protein aggregation in Saccharomyces cerevisiae

Exposure to selenomethionine causes selenocysteine misincorporation and protein aggregation in Saccharomyces cerevisiae

Growth inhibition by selenium is associated with changes in primary metabolism and nutrient levels in Arabidopsis thaliana

Recent advances in the mechanism of selenoamino acids toxicity in eukaryotic cells

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