Endoplasmic reticulum is a major target of cadmium toxicity in yeast.
Cadmium (Cd(2+)) is a very toxic metal that causes DNA damage, oxidative stress and apoptosis. Despite many studies, the cellular and molecular mechanisms underlying its high toxicity are not clearly understood. We show here that very low doses of Cd(2+) cause ER stress in Saccharomyces cerevisiae as evidenced by the induction of the unfolded protein response (UPR) and the splicing of HAC1 mRNA. Furthermore, mutant strains (Delta ire1 and Delta hac1) unable to induce the UPR are hypersensitive to Cd(2+), but not to arsenite and mercury. The full functionality of the pathways involved in ER stress response is required for Cd(2+) tolerance. The data also suggest that Cd(2+)-induced ER stress and Cd(2+) toxicity are a direct consequence of Cd(2+) accumulation in the ER. Cd(2+) does not inhibit disulfide bond formation but perturbs calcium metabolism. In particular, Cd(2+) activates the calcium channel Cch1/Mid1, which also contributes to Cd(2+) entry into the cell. The results reinforce the interest of using yeast as a cellular model to study toxicity mechanisms in eukaryotic cells.
Gardarin
Aurélie
A
Equipe Transports et Régulations Intracellulaires de Métaux, LCBM/iRTSV, CEA/Grenoble, 17 rue des Martyrs, F-38054 Grenoble Cedex 9, France.
Chédin
Stéphane
S
Lagniel
Gilles
G
Aude
Jean-Christophe
JC
Godat
Emmanuel
E
Catty
Patrice
P
Labarre
Jean
J
D002104:Cadmium / Q000378:metabolism / Q000633:toxicity*; D015220:Calcium Channels / Q000378:metabolism; D025141:Drug Resistance, Fungal; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000819:agonists / Q000378:metabolism; D017510:Protein Folding; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000648:ultrastructure; D029701:Saccharomyces cerevisiae Proteins / Q000819:agonists / Q000378:metabolism; D013312:Stress, Physiological
C108765:CCH1 protein, S cerevisiae; D015220:Calcium Channels; C090463:MID1 protein, S cerevisiae; D008562:Membrane Glycoproteins; D029701:Saccharomyces cerevisiae Proteins; D002104:Cadmium