Cryptococcus neoformans is one of the few environmental fungi that can survive within a mammalian host and cause disease. Although many of the factors responsible for establishing virulence have been recognized, how they are expressed in response to certain host-derived cellular stresses is rarely addressed. Here, we characterize the temporal translational response of C. neoformans to oxidative stress. We find that translation is largely inhibited through the phosphorylation of the critical initiation factor eIF2α (α subunit of eukaryotic initiation factor 2) by a sole kinase. Preventing eIF2α-mediated translational suppression resulted in growth sensitivity to hydrogen peroxide (H2O2). Our work suggests that translational repression in response to H2O2 partly facilitates oxidative stress adaptation by accelerating the decay of abundant non-stress-related transcripts while facilitating the proper expression levels of select oxidative stress response factors. Our results illustrate translational suppression as a critical determinant of select mRNA decay, gene expression, and subsequent survival in response to oxidative stress.IMPORTANCE Fungal survival in a mammalian host requires the coordinated expression and downregulation of a large cohort of genes in response to cellular stresses. Initial infection with C. neoformans occurs in the lungs, where it interacts with host macrophages. Surviving macrophage-derived cellular stresses, such as the production of reactive oxygen and nitrogen species, is believed to promote dissemination into the central nervous system. Therefore, investigating how an oxidative stress-resistant phenotype is brought about in C. neoformans not only furthers our understanding of fungal pathogenesis but also unveils mechanisms of stress-induced gene reprogramming. We discovered that H2O2-derived oxidative stress resulted in severe translational suppression and that this suppression was necessary for the accelerated decay and expression of tested transcripts.

中文翻译：

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翻译调控促进人类病原体新型隐球菌的氧化应激抵抗力。

新型隐球菌是少数能够在哺乳动物宿主体内存活并引起疾病的环境真菌之一。尽管许多导致毒力建立的因素已被认识，但它们如何表达以响应某些宿主衍生的细胞应激却很少得到解决。在这里，我们描述了新型隐球菌对氧化应激的时间翻译反应。我们发现翻译在很大程度上是通过单一激酶对关键起始因子 eIF2α（真核起始因子 2 的 α 亚基）的磷酸化而受到抑制。防止 eIF2α 介导的翻译抑制导致生长对过氧化氢 (H2O2) 敏感。我们的工作表明，对 H2O2 的翻译抑制通过加速丰富的非应激相关转录本的衰减，同时促进选定的氧化应激反应因子的适当表达水平，在一定程度上促进了氧化应激适应。我们的结果表明，翻译抑制是选择性 mRNA 衰减、基因表达和随后响应氧化应激而存活的关键决定因素。 重要性 哺乳动物宿主中的真菌生存需要大量基因的协调表达和下调，以响应细胞应激。新型隐球菌的初始感染发生在肺部，在那里它与宿主巨噬细胞相互作用。据信，幸存的巨噬细胞衍生的细胞应激，例如活性氧和氮的产生，可以促进传播到中枢神经系统。因此，研究新型隐球菌如何产生氧化应激抗性表型不仅可以进一步加深我们对真菌发病机制的理解，还可以揭示应激诱导的基因重编程机制。我们发现 H2O2 衍生的氧化应激导致严重的翻译抑制，并且这种抑制对于测试转录本的加速衰减和表达是必要的。