Cadmium impairs protein folding in the endoplasmic reticulum and induces the unfolded protein response.
Cellular exposure to cadmium is known to strongly induce the unfolded protein response (UPR), which suggests that the endoplasmic reticulum (ER) is preferentially damaged by cadmium. According to recent reports, the UPR is induced both dependent on and independently of accumulation of unfolded proteins in the ER. In order to understand the toxic mechanism of cadmium, here we investigated how cadmium exposure leads to Ire1 activation, which triggers the UPR, using yeast Saccharomyces cerevisiae as a model organism. Cadmium poorly induced the UPR when Ire1 carried a mutation that impairs its ability to recognize unfolded proteins. Ire1 activation by cadmium was also attenuated by the chemical chaperone 4-phenylbutyrate. Cadmium caused sedimentation of BiP, the molecular chaperone in the ER, which suggests the ER accumulation of unfolded proteins. A green fluorescent protein-based reporter assay also indicated that cadmium damages the oxidative protein folding in the ER. We also found that an excess concentration of extracellular calcium attenuates the Ire1 activation by cadmium. Taken together, we propose that cadmium exposure leads to the UPR induction through impairment of protein folding in the ER.
Graduate School of Biological Sciences, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara 630-0192, Japan.
Quynh Giang
QG
Le
Graduate School of Biological Sciences, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara 630-0192, Japan.
Yuki
Y
Ishiwata-Kimata
Graduate School of Biological Sciences, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara 630-0192, Japan.
Kenji
K
Kohno
Graduate School of Biological Sciences, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara 630-0192, Japan kimata@bs.naist.jp.
Yukio
Y
Kimata
D002104:Cadmium / Q000633:toxicity*; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism*; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000032:analysis / Q000235:genetics; D008562:Membrane Glycoproteins / Q000378:metabolism; D017510:Protein Folding / Q000187:drug effects*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D015533:Transcriptional Activation; D056811:Unfolded Protein Response / Q000187:drug effects*
D008562:Membrane Glycoproteins; D029701:Saccharomyces cerevisiae Proteins; D002104:Cadmium; D049452:Green Fluorescent Proteins; C082863:IRE1 protein, S cerevisiae; D017346:Protein Serine-Threonine Kinases
UPR; cadmium; endoplasmic reticulum; heavy metal; molecular chaperone; organelle