Peralta Daiana Romina, Farizano Juan Vicente, Bulacio Gil Natalia, Corbalán Natalia Soledad, Pomares María Fernanda, Vincent Paula Andrea, Adler Conrado
Instituto Superior de Investigaciones Biológicas (INSIBIO), CONICET-UNT and Instituto de Química Biológica "Dr. Bernabé Bloj", Facultad de Bioquímica, Química y Farmacia, UNT, Tucumán, Argentina.
Front Mol Biosci. 2022 Aug 16;9:961917. doi: 10.3389/fmolb.2022.961917. eCollection 2022.
The ability of siderophores to play roles beyond iron acquisition has been recently proven for many of them and evidence continues to grow. An earlier work showed that the siderophore enterobactin is able to increase copper toxicity by reducing Cu to Cu, a form of copper that is more toxic to cells. Copper toxicity is multifaceted. It involves the formation of reactive oxygen species (ROS), mismetallation of enzymes and possibly other mechanisms. Given that we previously reported on the capacity of enterobactin to alleviate oxidative stress caused by various stressors other than copper, we considered the possibility that the siderophore could play a dual role regarding copper toxicity. In this work, we show a bimodal effect of enterobactin on copper toxicity (protective and harmful) which depends on the siderophore concentration. We found that the absence of enterobactin rendered cells more sensitive to copper, due to the reduced ability of those cells to cope with the metal-generated ROS. Consistently, addition of low concentrations of the siderophore had a protective effect by reducing ROS levels. We observed that in order to achieve this protection, enterobactin had to enter cells and be hydrolyzed in the cytoplasm. Further supporting the role of enterobactin in oxidative stress protection, we found that both oxygen and copper, induced the expression of the siderophore and also found that copper strongly counteracted the well-known downregulation effect of iron on enterobactin synthesis. Interestingly, when enterobactin was present in high concentrations, cells became particularly sensitive to copper most likely due to the Cu to Cu reduction, which increased the metal toxicity leading to cell death.
最近已证实，许多铁载体除了具有获取铁的功能外，还能发挥其他作用，而且相关证据不断增加。早期的一项研究表明，铁载体肠杆菌素能够通过将铜还原为Cu（一种对细胞毒性更强的铜形式）来增强铜的毒性。铜毒性是多方面的。它涉及活性氧（ROS）的形成、酶的金属错配以及可能的其他机制。鉴于我们之前报道过肠杆菌素能够减轻除铜之外的各种应激源所引起的氧化应激，我们考虑了这种铁载体在铜毒性方面可能发挥双重作用的可能性。在这项研究中，我们展示了肠杆菌素对铜毒性具有双相效应（保护性和有害性），这取决于铁载体的浓度。我们发现，缺乏肠杆菌素会使细胞对铜更敏感，因为这些细胞应对金属产生的ROS的能力降低。一致的是，添加低浓度的铁载体通过降低ROS水平具有保护作用。我们观察到，为了实现这种保护，肠杆菌素必须进入细胞并在细胞质中水解。进一步支持肠杆菌素在氧化应激保护中的作用，我们发现氧气和铜都会诱导铁载体的表达，并且还发现铜强烈抵消了铁对肠杆菌素合成的众所周知的下调作用。有趣的是，当肠杆菌素浓度较高时，细胞对铜变得特别敏感，这很可能是由于Cu向Cu的还原，从而增加了金属毒性导致细胞死亡。
