Cryptococcus neoformans Iron-Sulfur Protein Biogenesis Machinery Is a Novel Layer of Protection against Cu Stress.
Cryptococcus neoformans Iron-Sulfur Protein Biogenesis Machinery Is a Novel Layer of Protection against Cu Stress.
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DOI：
10.1128/mbio.01742-17
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发表时间：
2017-10-31
期刊：
影响因子：
6.4
通讯作者：
Thiele DJ
中科院分区：
文献类型：
--
作者：
Garcia-Santamarina S;Uzarska MA;Festa RA;Lill R;Thiele DJ
铜离子是驱动关键生化过程的催化辅因子，然而，超过细胞内平衡控制能力的铜水平是有毒的。铜中毒的潜在机制尚不清楚。在新生隐球菌的肺部感染过程中，宿主肺泡巨噬细胞将铜分隔到吞噬小体中，解毒铜的能力对其生存和毒力至关重要。在这里，我们报告了铁-硫(Fe-S)簇是铜毒性的关键靶标，在酿酒酵母和新生葡萄球菌中，这种作用取决于铜对铁-S辅因子的可及性。为了响应这种铜依赖的铁-S胁迫，新生隐球菌诱导线粒体ABC转运蛋白Atm1的转录，该转运蛋白在胞核-胞核Fe-S蛋白的生物发生中作用于铜，并依赖于铜金属调控转录因子Cuf1。由于Atm1的功能是将Fe-S前体从线粒体基质输出到细胞质中，因此，缺失Atm1的新生梭菌细胞对铜敏感，即使铜解毒的金属硫蛋白蛋白高度表达。我们提供了以前未知的微生物防御机制来应对铜中毒的证据，我们强调了新生隐孢子菌具有几种不同的机制来应对铜中毒的重要性，这些机制共同有助于这种微生物作为一种机会性的人类真菌病原体的成功。金黄色葡萄球菌是一种机会性病原体，每年导致超过65万人患上致命性脑膜炎。使用有毒或效果不佳的全身性抗真菌药物以及诊断困难，进一步加剧了新生隐球菌属感染的严重性。铜是一种天然的强效抗菌剂，它被分隔在巨噬细胞吞噬小体内，并被天然免疫细胞用来中和微生物病原体。虽然新生隐孢子虫的铜解毒机制对于毒力是必不可少的，但人们对铜杀死真菌的机制知之甚少。在这里，我们报道了含Fe-S簇的蛋白，包括Fe-S蛋白生物发生机制本身的成员，是铜毒性的关键靶标，因此这种生物合成过程提供了抵御高铜水平的重要保护层。鉴于铜离子载体作为抗菌剂的作用，了解铜对微生物的毒性可以导致开发有效的广谱抗菌剂。此外，了解铜的毒性可以为人类铜过量疾病(如威尔逊病)的病理生理学提供更多的见解。
Copper (Cu) ions serve as catalytic cofactors to drive key biochemical processes, and yet Cu levels that exceed cellular homeostatic control capacity are toxic. The underlying mechanisms for Cu toxicity are poorly understood. During pulmonary infection by the fungal pathogen Cryptococcus neoformans, host alveolar macrophages compartmentalize Cu to the phagosome, and the ability to detoxify Cu is critical for its survival and virulence. Here, we report that iron-sulfur (Fe-S) clusters are critical targets of Cu toxicity in both Saccharomyces cerevisiae and C. neoformans in a manner that depends on the accessibility of Cu to the Fe-S cofactor. To respond to this Cu-dependent Fe-S stress, C. neoformans induces the transcription of mitochondrial ABC transporter Atm1, which functions in cytosolic-nuclear Fe-S protein biogenesis in response to Cu and in a manner dependent on the Cu metalloregulatory transcription factor Cuf1. As Atm1 functions in exporting an Fe-S precursor from the mitochondrial matrix to the cytosol, C. neoformans cells depleted for Atm1 are sensitive to Cu even while the Cu-detoxifying metallothionein proteins are highly expressed. We provide evidence for a previously unrecognized microbial defense mechanism to deal with Cu toxicity, and we highlight the importance for C. neoformans of having several distinct mechanisms for coping with Cu toxicity which together could contribute to the success of this microbe as an opportunistic human fungal pathogen. C. neoformans is an opportunistic pathogen that causes lethal meningitis in over 650,000 people annually. The severity of C. neoformans infections is further compounded by the use of toxic or poorly effective systemic antifungal agents as well as by the difficulty of diagnosis. Cu is a natural potent antimicrobial agent that is compartmentalized within the macrophage phagosome and used by innate immune cells to neutralize microbial pathogens. While the Cu detoxification machinery of C. neoformans is essential for virulence, little is known about the mechanisms by which Cu kills fungi. Here we report that Fe-S cluster-containing proteins, including members of the Fe-S protein biogenesis machinery itself, are critical targets of Cu toxicity and therefore that this biosynthetic process provides an important layer of defense against high Cu levels. Given the role of Cu ionophores as antimicrobials, understanding how Cu is toxic to microorganisms could lead to the development of effective, broad-spectrum antimicrobials. Moreover, understanding Cu toxicity could provide additional insights into the pathophysiology of human diseases of Cu overload such as Wilson’s disease.