Pho4 mediates phosphate acquisition in Candida albicans and is vital for stress resistance and metal homeostasis.
Pho4 mediates phosphate acquisition in Candida albicans and is vital for stress resistance and metal homeostasis.
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DOI：
10.1091/mbc.e16-05-0266
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发表时间：
2016-09-01
影响因子：
3.3
通讯作者：
Quinn J
中科院分区：
文献类型：
--
作者：
Ikeh MA;Kastora SL;Day AM;Herrero-de-Dios CM;Tarrant E;Waldron KJ;Banks AP;Bain JM;Lydall D;Veal EA;MacCallum DM;Erwig LP;Brown AJ;Quinn J
这项研究提供了第一个证据表明，磷酸盐响应转录因子Pho 4是至关重要的白念珠菌的生存多样化和生理相关的压力。Pho 4对C.因此，这些发现说明代谢适应如何促进C。白色念珠菌在宿主体内存活。在与哺乳动物宿主的相互作用过程中，致病酵母白色念珠菌暴露于一系列压力，例如超氧自由基和阳离子通量。出乎意料的是，转录因子缺失突变体的无偏倚筛选揭示了磷酸盐响应转录因子Pho 4对于C.白色念珠菌对这些不同的压力。RNA-Seq分析表明，Pho 4不直接诱导胁迫保护基因。相反，我们表明，损失的Pho 4影响金属阳离子的毒性，积累和生物利用度。我们证明了pho 4 Δ细胞对金属和非金属阳离子敏感，并且pho 4介导的多磷酸盐合成介导了锰抗性。值得注意的是，我们表明，Pho 4是重要的介导铜的生物利用度，以支持铜/锌超氧化物歧化酶Sod 1的活性和Sod 1活性的损失有助于pho 4 Δ细胞的超氧化物敏感性。与真菌应激反应在对抗宿主吞噬防御中的关键作用一致，我们还报道了C。白色念珠菌pho 4 Δ细胞对巨噬细胞介导的杀伤非常敏感，并且在动物感染模型中显示出减弱的毒力。本研究中提出的磷酸盐代谢、金属稳态和超氧化物胁迫抗性之间的新联系强调了代谢适应在促进C。白色念珠菌在宿主体内存活。
This study provides the first evidence that the phosphate-responsive transcription factor Pho4 is vital for survival of Candida albicans to diverse and physiologically relevant stresses. Pho4 is important for C. albicans pathogenesis, and thus these findings illustrate how metabolic adaptation promotes C. albicans survival in the host. During interactions with its mammalian host, the pathogenic yeast Candida albicans is exposed to a range of stresses such as superoxide radicals and cationic fluxes. Unexpectedly, a nonbiased screen of transcription factor deletion mutants revealed that the phosphate-responsive transcription factor Pho4 is vital for the resistance of C. albicans to these diverse stresses. RNA-Seq analysis indicated that Pho4 does not induce stress-protective genes directly. Instead, we show that loss of Pho4 affects metal cation toxicity, accumulation, and bioavailability. We demonstrate that pho4Δ cells are sensitive to metal and nonmetal cations and that Pho4-mediated polyphosphate synthesis mediates manganese resistance. Significantly, we show that Pho4 is important for mediating copper bioavailability to support the activity of the copper/zinc superoxide dismutase Sod1 and that loss of Sod1 activity contributes to the superoxide sensitivity of pho4Δ cells. Consistent with the key role of fungal stress responses in countering host phagocytic defenses, we also report that C. albicans pho4Δ cells are acutely sensitive to macrophage-mediated killing and display attenuated virulence in animal infection models. The novel connections between phosphate metabolism, metal homeostasis, and superoxide stress resistance presented in this study highlight the importance of metabolic adaptation in promoting C. albicans survival in the host.