Sánchez Clara Inés, Díaz Verónica, Alcázar Laura, Amich Jorge, Marín Laura, Calera José Antonio
Instituto de Biología Funcional y Genómica (IBFG-CSIC), Universidad de Salamanca, Salamanca, Spain.
Laboratorio de Referencia e Investigación en Micología, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Madrid, Spain.
Microbiol Spectr. 2025 Sep 23:e0227925. doi: 10.1128/spectrum.02279-25.
The filamentous fungus is equipped with an efficient zinc uptake system that allows this fungus to survive and grow within the very zinc-limiting environment provided by the lungs of immunosuppressed patients. To deal with zinc scarcity, deploys a homeostatic and adaptive response that enables it to scavenge for and uptake zinc from host tissues. Finally, zinc ions are distributed intracellularly and lodged in fungal proteins that require them for normal functioning. It is believed that most zinc-requiring proteins acquire zinc ions to become properly metalated by competition with cellular zinc proteins. However, certain zinc proteins may exhibit inherent thermodynamic and/or physicochemical properties that hamper them from competing for zinc with other proteins during zinc deficiency, such that they can only be properly metalated if aided by specific metallochaperones. In this study, we report a comprehensive approach to the role of the zinc metallochaperones of (MchA, MchB, and MchC) on both fungal physiology during zinc deficiency and fungal pathogenesis. Our data suggest that MchA might play a role in supplying zinc to one or more proteins operating in a biosynthetic pathway that use tetrahydrofolate (THF) as a cofactor; MchB is required for reactive oxygen species (ROS) production as an adaptive response to zinc deficiency, whereas MchC plays a role in THF biosynthesis, most likely by supplying zinc to GTP cyclohydrolase I. This is the first study that provides insights into the role of zinc-metallochaperones in a fungal pathogen and how they could be exploited as antifungal targets.IMPORTANCE is able to suppress nutritional immunity and obtain zinc from the lungs of immunosuppressed patients, allowing it to grow and cause invasive pulmonary aspergillosis. To combat this lethal infection, there is an urgent need for new antifungals. In this regard, tetrahydrofolate (THF) biosynthesis is a promising target. However, antifungal drugs against this process have not been developed yet, likely because only a few antifolates used as antibacterials are also active against a limited number of fungal pathogens. Our research may provide the explanation of the sensitivity to antifolates of those pathogens (, and ), being that all lack MchC-like proteins. Moreover, we foresee that inhibition of THF biosynthesis in MchC-bearing fungal pathogens could be enhanced by inhibiting MchC activity. Also, our findings suggest the notion that ROS overproduction typically occurring in all cells during zinc deficiency may rely on proper metalation of certain zinc-dependent proteins.
丝状真菌具备高效的锌摄取系统，这使得该真菌能够在免疫抑制患者肺部提供的锌极度匮乏的环境中存活和生长。为应对锌短缺，它会启动一种稳态和适应性反应，使其能够从宿主组织中搜寻并摄取锌。最后，锌离子在细胞内分布，并存在于正常功能所需的真菌蛋白质中。据信，大多数需要锌的蛋白质通过与细胞内锌蛋白竞争来获取锌离子，从而实现正确的金属化。然而，某些锌蛋白可能具有内在的热力学和/或物理化学特性，在锌缺乏时阻碍它们与其他蛋白质竞争锌，以至于只有在特定金属伴侣蛋白的帮助下才能实现正确的金属化。在本研究中，我们报告了一种全面的方法，研究了（MchA、MchB和MchC）的锌金属伴侣蛋白在锌缺乏期间对真菌生理和真菌致病性的作用。我们的数据表明，MchA可能在为一个或多个在以四氢叶酸（THF）为辅因子的生物合成途径中起作用的蛋白质供应锌方面发挥作用；MchB是作为对锌缺乏的适应性反应产生活性氧（ROS）所必需的，而MchC在THF生物合成中起作用，很可能是通过向GTP环化水解酶I供应锌来实现的。这是第一项深入了解锌金属伴侣蛋白在真菌病原体中的作用以及它们如何被开发为抗真菌靶点的研究。重要性在于能够抑制营养免疫并从免疫抑制患者的肺部获取锌，使其得以生长并引发侵袭性肺曲霉病。为对抗这种致命感染，迫切需要新型抗真菌药物。在这方面，四氢叶酸（THF）生物合成是一个有前景的靶点。然而，针对这一过程的抗真菌药物尚未开发出来，可能是因为只有少数用作抗菌剂的抗叶酸药物对有限数量的真菌病原体也有活性。我们的研究可能解释了那些病原体（、和）对抗叶酸药物敏感的原因，因为它们都缺乏类似MchC的蛋白质。此外，我们预计，通过抑制MchC活性，可以增强对携带MchC的真菌病原体中THF生物合成的抑制作用。而且，我们的研究结果表明，在锌缺乏期间所有细胞中通常发生的ROS过度产生可能依赖于某些锌依赖性蛋白质的正确金属化。
