College of Biomedicine and Health, Huazhong Agricultural University, Wuhan, Hubei, 430070, China.
College of Fisheries, Huazhong Agricultural University, Wuhan, Hubei, 430070, China.
Ecotoxicol Environ Saf. 2023 Nov 1;266:115571. doi: 10.1016/j.ecoenv.2023.115571. Epub 2023 Oct 13.
Cadmium toxicity has been associated with disruption of protein homeostasis by interfering with protein folding processes. Heat shock factor 1 (HSF1) coordinates the rapid and extensive cellular response to maintain proteomic balance facing the challenges from many environmental stressors. Thus, we suspect that HSF1 may shield cells from cadmium toxicity by conserving proteome integrity.
Here, we demonstrate that cadmium, a highly poisonous metal, induces aggregation of cytosolic proteins in human cells, which disrupts protein homeostasis and activates HSF1. Cadmium exposure increases HSF1's phosphorylation, nuclear translocation and DNA bindings. Aside from this, HSF1 goes through liquid-liquid phase separation to form small nuclear condensates upon cadmium exposure. A specific regulatory domain of HSF1 is critical for HSF1's phase separation capability. Most importantly, human cells with impaired HSF1 are sensitized to cadmium, however, cells with overexpressed HSF1 are protected from cadmium toxicity. Overexpression of HSF1 in human cells reduces protein aggregates, amyloid fibrils and DNA damages to antagonize cadmium toxicity.
HSF1 protects cells from cadmium toxicity by governing the integrity of both proteome and genome. Similar mechanisms may enable HSF1 to alleviate cellular toxicity caused by other heavy metals. HSF1's role in cadmium exposure may provide important insights into the toxic effects of heavy metals on human cells and body organs, allowing us to better manage heavy metal poisoning.
镉毒性通过干扰蛋白质折叠过程而导致蛋白质稳态紊乱，与这种毒性有关。热休克因子 1（HSF1）通过协调快速而广泛的细胞反应来维持蛋白质组平衡，以应对来自许多环境胁迫因素的挑战。因此，我们推测 HSF1 可能通过保护蛋白质组的完整性来保护细胞免受镉毒性。
在这里，我们证明了镉，一种剧毒金属，会诱导人细胞胞质蛋白聚集，从而破坏蛋白质稳态并激活 HSF1。镉暴露会增加 HSF1 的磷酸化、核转位和 DNA 结合。除此之外，HSF1 还会发生液-液相分离，在暴露于镉时形成小核凝聚物。HSF1 的一个特定调节域对于 HSF1 的相分离能力至关重要。最重要的是，HSF1 功能受损的人类细胞对镉更加敏感，而过表达 HSF1 的细胞则能免受镉毒性的影响。在人细胞中过表达 HSF1 可减少蛋白质聚集体、淀粉样纤维和 DNA 损伤，从而拮抗镉毒性。
HSF1 通过维持蛋白质组和基因组的完整性来保护细胞免受镉毒性。类似的机制可能使 HSF1 能够减轻其他重金属对细胞的毒性作用。HSF1 在镉暴露中的作用为深入了解重金属对人类细胞和器官的毒性作用提供了重要的见解，使我们能够更好地管理重金属中毒。
