Department of Biochemistry and Molecular Biology, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA.
Department of Ophthalmology, University of Missouri, Columbia, MO 65211, USA.
J Inorg Biochem. 2021 Jun;219:111424. doi: 10.1016/j.jinorgbio.2021.111424. Epub 2021 Mar 15.
Copper is an essential metal for virtually all organisms, yet little is known about the extracellular sources of this micronutrient. In serum, the most abundant extracellular Cu-binding molecule is the multi‑copper oxidase ceruloplasmin (Cp). Cp levels increase during infection and inflammation, and pathogens can be exposed to high Cp at sites of infection. It is not known whether Cp might serve as a Cu source for microbial pathogens and we tested this using the opportunistic fungal pathogen Candida albicans. We find that C. albicans can use whole serum as a Cu source and that this Cu is sensed by the transcription factor protein Mac1. Mac1 activates expression of Mn-SOD3 superoxide dismutase and represses Cu/Zn-SOD1 during Cu starvation and both responses are regulated by serum Cu. We also show that purified human Cp can act as a sole source of Cu for the fungus and likewise modulates the Mac1 Cu stress response. To investigate whether Cp is a Cu source in serum, we compared the ability of C. albicans to use serum from wild type versus Cp mutant mice. We find that serum lacking Cp is deficient in its ability to trigger the Mac1 Cu response. C. albicans did accumulate Cu from Cp serum, but this Cu was not efficiently sensed by Mac1. We conclude that Cp and non-Cp Cu sources are not equivalent and are handled differently by the fungal cell. Overall, these studies are the first to show that Cp is a preferred source of Cu for a pathogen.
铜是几乎所有生物体必需的金属，但对于这种微量元素的细胞外来源知之甚少。在血清中，最丰富的细胞外 Cu 结合分子是多铜氧化酶铜蓝蛋白（Cp）。Cp 水平在感染和炎症期间增加，病原体在感染部位可能会暴露于高浓度的 Cp 下。目前尚不清楚 Cp 是否可以作为微生物病原体的 Cu 来源，我们使用机会性真菌病原体白色念珠菌对此进行了测试。我们发现，白色念珠菌可以利用整个血清作为 Cu 来源，而这种 Cu 被转录因子蛋白 Mac1 感知。Mac1 在 Cu 饥饿时激活 Mn-SOD3 超氧化物歧化酶的表达并抑制 Cu/Zn-SOD1，这两种反应都受血清 Cu 的调节。我们还表明，纯化的人 Cp 可以作为真菌的唯一 Cu 来源，并同样调节 Mac1 的 Cu 应激反应。为了研究 Cp 是否是血清中的 Cu 来源，我们比较了野生型和 Cp 突变小鼠血清对白色念珠菌的使用能力。我们发现缺乏 Cp 的血清在触发 Mac1 Cu 反应方面能力不足。白色念珠菌确实从 Cp 血清中积累了 Cu，但 Mac1 对这种 Cu 的感知效率较低。我们得出结论，Cp 和非 Cp Cu 来源并不等效，并且真菌细胞对它们的处理方式不同。总的来说，这些研究首次表明 Cp 是病原体的首选 Cu 来源。
