Toh-E Akio, Ohkusu Misako, Ishiwada Naruhiko, Watanabe Akira, Kamei Katsuhiko
Medical Mycology Research Center, Chiba University, 1-8-1 Inohana, Chiba, 260-8673, Japan.
Curr Genet. 2022 Feb;68(1):125-141. doi: 10.1007/s00294-021-01222-y. Epub 2021 Nov 10.
Cryptococcus neoformans, basidiomycetous pathogenic yeast, is basically an environmental fungus and, therefore, challenged by ever changing environments. In this study, we focused on how C. neoformans responds to stress caused by cadmium that is one of high-risk pollutants. By tracking phenotypes of the resistance or sensitivity to cadmium, we undertook forward and reverse genetic studies to identify genes involved in cadmium metabolism in C. neoformans. We found that the main route of Cd influx is through Mn ion transporter, Smf1, which is an ortholog of Nramp (natural resistance-associated macrophage protein 1) of mouse. We found that serotype A strains are generally more resistant to cadmium than serotype D strains and that cadmium resistance of H99, a representative of serotype A strains, was found to be due to a partial defect in SMF1. We found that calcium channel has a subsidiary role for cadmium uptake. We also showed that Pca1 (P-type-ATPase) functions as an extrusion pump for cadmium. We examined the effects of some metals on cadmium toxicity and suggested (i) that Ca and Zn could exert their protective function against Cd via restoring cadmium-inhibited cellular processes and (ii) that Mg and Mn could have antagonistic roles in an unknown Smf1-independent Cd uptake system. We proposed a model for Cd2-response of C. neoformans, which will serve as a platform for understanding how this organism copes with the toxic metal.
新型隐球菌是担子菌致病性酵母，本质上是一种环境真菌，因此受到不断变化的环境的挑战。在本研究中，我们聚焦于新型隐球菌如何应对由镉（一种高风险污染物）引起的胁迫。通过追踪对镉的抗性或敏感性表型，我们进行了正向和反向遗传学研究，以鉴定新型隐球菌中参与镉代谢的基因。我们发现镉流入的主要途径是通过锰离子转运蛋白Smf1，它是小鼠Nramp（天然抗性相关巨噬细胞蛋白1）的直系同源物。我们发现A型血清型菌株通常比D型血清型菌株对镉更具抗性，并且发现A型血清型菌株的代表H99对镉的抗性是由于SMF1存在部分缺陷。我们发现钙通道在镉摄取中起辅助作用。我们还表明Pca1（P型ATP酶）作为镉的外排泵发挥作用。我们研究了一些金属对镉毒性的影响，并提出（i）钙和锌可以通过恢复镉抑制的细胞过程来发挥对镉的保护作用，以及（ii）镁和锰可能在未知的不依赖Smf1的镉摄取系统中具有拮抗作用。我们提出了一个新型隐球菌对镉响应的模型，这将作为理解该生物体如何应对有毒金属的平台。
