scholarly journals Characterization and functional significance of Msc2p and Zrg17p, which form a zinc transport complex in the endoplasmic reticulum of Saccharomyces cerevisiae

2004 ◽  
Author(s):  
◽  
Charissa D. Ellis
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Endoplasmic Reticulum ◽  
Zinc Deficiency ◽  
Zinc Homeostasis ◽  
Zinc Transport ◽  
Cation Diffusion ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Transport Complex

We demonstrate a novel interaction between two members of the cation diffusion facilitator (CDF) family in Saccharomyces cerevisiae: Msc2p and a newly recognized CDF family member, Zrg17p. Both Msc2p and Zrg17p have been previously implicated in zinc homeostasis in yeast. In particular, ZRG17 was previously identified as a zinc regulated gene controlled by the zinc-responsive Zap1p transcription factor. We show that both Msc2p and Zrg17p are localized to the endoplasmic reticulum (ER) when expressed at normal levels. Zinc deficiency in yeast induces the unfolded protein response (UPR), a system normally activated by unfolded ER proteins. UPR induction in low zinc is exacerbated in msc2 and zrg17 mutants. Genetic and biochemical evidence indicate that this UPR induction is due to genuine ER dysfunction. Notably, ER-associated protein degradation (ERAD) is defective in zinc-limited msc2 mutants. Msc2p and Zrg17p physically interact, as determined by co-immunoprecipitation. Therefore, we propose that Msc2p and Zrg17p form a zinc transport complex in the ER membrane to maintain the function of this compartment. Zinc deficiency also upregulates the mammalian ER stress response, indicating a conserved requirement for zinc in ER function among eukaryotes. Lastly, ZnT5 and ZnT6, the closest mammalian homologues to Msc2p and Zrg17p, may also functionally interact, suggesting that interactions between CDF members may be a common phenomenon.We demonstrate a novel interaction between two members of the cation diffusion.

scholarly journals Zinc and the Msc2 zinc transporter protein are required for endoplasmic reticulum function

2004 ◽  
Vol 166 (3) ◽  
pp. 325-335 ◽  
Author(s):  
Charissa D. Ellis ◽  
Fudi Wang ◽  
Colin W. MacDiarmid ◽  
Suzanne Clark ◽  
Thomas Lyons ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Zinc Deficiency ◽  
Metal Ion ◽  
Zinc Homeostasis ◽  
Cation Diffusion ◽  
Transporter Protein ◽  
Unfolded Protein ◽  
Er Stress Response ◽  
The Unfolded Protein Response ◽  
Protein Response

In this report, we show that zinc is required for endoplasmic reticulum function in Saccharomyces cerevisiae. Zinc deficiency in this yeast induces the unfolded protein response (UPR), a system normally activated by unfolded ER proteins. Msc2, a member of the cation diffusion facilitator (CDF) family of metal ion transporters, was previously implicated in zinc homeostasis. Our results indicate that Msc2 is one route of zinc entry into the ER. Msc2 localizes to the ER when expressed at normal levels. UPR induction in low zinc is exacerbated in an msc2 mutant. Genetic and biochemical evidence indicates that this UPR induction is due to genuine ER dysfunction. Notably, we found that ER-associated protein degradation is defective in zinc-limited msc2 mutants. We also show that the vacuolar CDF proteins Zrc1 and Cot1 are other pathways of ER zinc acquisition. Finally, zinc deficiency up-regulates the mammalian ER stress response indicating a conserved requirement for zinc in ER function among eukaryotes.

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

2021 ◽  
Vol 22 (11) ◽  
pp. 5467
Author(s):  
Marc Dauplais ◽  
Pierre Mahou ◽  
Pierre Plateau ◽  
Myriam Lazard
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Endoplasmic Reticulum ◽  
Disulfide Bonds ◽  
Protein Misfolding ◽  
Carboxypeptidase Y ◽  
Unfolded Protein ◽  
Er Chaperone ◽  
Concomitant Reduction ◽  
The Unfolded Protein Response ◽  
Protein Response

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.

scholarly journals The Effects of Bergamot Polyphenolic Fraction, Cynara cardunculus, and Olea europea L. Extract on Doxorubicin-Induced Cardiotoxicity

Nutrients ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 2158
Author(s):  
Jessica Maiuolo ◽  
Irene Bava ◽  
Cristina Carresi ◽  
Micaela Gliozzi ◽  
Vincenzo Musolino ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Apoptotic Cell ◽  
Natural Compounds ◽  
Cynara Cardunculus ◽  
Unfolded Protein ◽  
Wide Range ◽  
Vitro Model ◽  
The Unfolded Protein Response ◽  
Protein Response

Doxorubicin is an anthracycline that is commonly used as a chemotherapy drug due to its cytotoxic effects. The clinical use of doxorubicin is limited due to its known cardiotoxic effects. Treatment with anthracyclines causes heart failure in 15–17% of patients, resulting in mitochondrial dysfunction, the accumulation of reactive oxygen species, intracellular calcium dysregulation, the deterioration of the cardiomyocyte structure, and apoptotic cell death. Polyphenols have a wide range of beneficial properties, and particular importance is given to Bergamot Polyphenolic Fraction; Oleuropein, one of the main polyphenolic compounds of olive oil; and Cynara cardunculus extract. These natural compounds have particular beneficial characteristics, owing to their high polyphenol contents. Among these, their antioxidant and antoproliferative properties are the most important. The aim of this paper was to investigate the effects of these three plant derivatives using an in vitro model of cardiotoxicity induced by the treatment of rat embryonic cardiomyoblasts (H9c2) with doxorubicin. The biological mechanisms involved and the crosstalk existing between the mitochondria and the endoplasmic reticulum were examined. Bergamot Polyphenolic Fraction, Oleuropein, and Cynara cardunculus extract were able to decrease the damage induced by exposure to doxorubicin. In particular, these natural compounds were found to reduce cell mortality and oxidative damage, increase the lipid content, and decrease the concentration of calcium ions that escaped from the endoplasmic reticulum. In addition, the direct involvement of this cellular organelle was demonstrated by silencing the ATF6 arm of the Unfolded Protein Response, which was activated after treatment with doxorubicin.

scholarly journals The unfolded protein response coordinates the production of endoplasmic reticulum protein and endoplasmic reticulum membrane.

1997 ◽  
Vol 8 (9) ◽  
pp. 1805-1814 ◽  
Author(s):  
J S Cox ◽  
R E Chapman ◽  
P Walter
Keyword(s):  
Endoplasmic Reticulum ◽  
Unfolded Protein Response ◽  
Secretory Pathway ◽  
Lipid Synthesis ◽  
Secretory Proteins ◽  
Endoplasmic Reticulum Membrane ◽  
Yeast Saccharomyces Cerevisiae ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

The endoplasmic reticulum (ER) is a multifunctional organelle responsible for production of both lumenal and membrane components of secretory pathway compartments. Secretory proteins are folded, processed, and sorted in the ER lumen and lipid synthesis occurs on the ER membrane itself. In the yeast Saccharomyces cerevisiae, synthesis of ER components is highly regulated: the ER-resident proteins by the unfolded protein response and membrane lipid synthesis by the inositol response. We demonstrate that these two responses are intimately linked, forming different branches of the same pathway. Furthermore, we present evidence indicating that this coordinate regulation plays a role in ER biogenesis.

scholarly journals An essential dimer-forming subregion of the endoplasmic reticulum stress sensor Ire1

2005 ◽  
Vol 391 (1) ◽  
pp. 135-142 ◽  
Author(s):  
Daisuke Oikawa ◽  
Yukio Kimata ◽  
Masato Takeuchi ◽  
Kenji Kohno
Keyword(s):  
Endoplasmic Reticulum ◽  
Recombinant Protein ◽  
Endoplasmic Reticulum Stress ◽  
Transmembrane Protein ◽  
Type I ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Recombinant Fragments ◽  
Made In

The luminal domain of the type I transmembrane protein Ire1 senses endoplasmic reticulum stress by an undefined mechanism to up-regulate the signalling pathway for the unfolded protein response. Previously, we proposed that the luminal domain of yeast Ire1 is divided into five subregions, termed subregions I–V sequentially from the N-terminus. Ire1 lost activity when internal deletions of subregion II or IV were made. In the present paper, we show that partial proteolysis of a recombinant protein consisting of the Ire1 luminal domain suggests that subregions II–IV are tightly folded. We also show that a recombinant protein of subregions II–IV formed homodimers, and that this homodimer formation was impaired by an internal deletion of subregion IV. Furthermore, recombinant fragments of subregion IV exhibited a self-binding ability. Therefore, although its sequence is little conserved evolutionarily, subregion IV plays an essential role to promote Ire1 dimer formation.

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