Jacobson Therese, Priya Smriti, Sharma Sandeep K, Andersson Stefanie, Jakobsson Sofia, Tanghe Robbe, Ashouri Arghavan, Rauch Sebastien, Goloubinoff Pierre, Christen Philipp, Tamás Markus J
Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden.
Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research, Lucknow, Uttar Pradesh, India.
Mol Cell Biol. 2017 Aug 11;37(17). doi: 10.1128/MCB.00490-16. Print 2017 Sep 1.
Cadmium is a highly poisonous metal and is classified as a human carcinogen. While its toxicity is undisputed, the underlying molecular mechanisms are not fully understood. Here, we demonstrate that cadmium induces aggregation of cytosolic proteins in living cells. Cadmium primarily targets proteins in the process of synthesis or folding, probably by interacting with exposed thiol groups in not-yet-folded proteins. On the basis of and data, we show that cadmium-aggregated proteins form seeds that increase the misfolding of other proteins. Cells that cannot efficiently protect the proteome from cadmium-induced aggregation or clear the cytosol of protein aggregates are sensitized to cadmium. Thus, protein aggregation may contribute to cadmium toxicity. This is the first report on how cadmium causes misfolding and aggregation of cytosolic proteins The proposed mechanism might explain not only the molecular basis of the toxic effects of cadmium but also the suggested role of this poisonous metal in the pathogenesis of certain protein-folding disorders.
镉是一种剧毒金属，被归类为人类致癌物。虽然其毒性无可争议，但其潜在的分子机制尚未完全了解。在此，我们证明镉会诱导活细胞中胞质蛋白聚集。镉主要靶向合成或折叠过程中的蛋白质，可能是通过与未折叠蛋白质中暴露的巯基相互作用。基于[此处缺失部分信息]和[此处缺失部分信息]数据，我们表明镉聚集的蛋白质形成种子，增加其他蛋白质的错误折叠。无法有效保护蛋白质组免受镉诱导聚集或清除蛋白质聚集体胞质溶胶的细胞对镉敏感。因此，蛋白质聚集可能导致镉毒性。这是关于镉如何导致胞质蛋白错误折叠和聚集的首次报告。所提出的机制不仅可能解释镉毒性作用的分子基础，还可能解释这种有毒金属在某些蛋白质折叠障碍发病机制中的作用。
