Fpa (YlaN) is an iron(II) binding protein that functions to relieve Fur-mediated repression of gene expression in Staphylococcus aureus.

IF 5.1 1区 生物学 Q1 MICROBIOLOGY mBio Pub Date : 2024-11-13 Epub Date: 2024-10-23 DOI:10.1128/mbio.02310-24
Jeffrey M Boyd, Kylie Ryan Kaler, Karla Esquilín-Lebrón, Ashley Pall, Courtney J Campbell, Mary E Foley, Gustavo Rios-Delgado, Emilee M Mustor, Timothy G Stephens, Hannah Bovermann, Todd M Greco, Ileana M Cristea, Valerie J Carabetta, William N Beavers, Debashish Bhattacharya, Eric P Skaar, Lindsey N Shaw, Timothy L Stemmler
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Abstract

Iron (Fe) is a trace nutrient required by nearly all organisms. As a result of the demand for Fe and the toxicity of non-chelated cytosolic ionic Fe, regulatory systems have evolved to tightly balance Fe acquisition and usage while limiting overload. In most bacteria, including the mammalian pathogen Staphylococcus aureus, the ferric uptake regulator (Fur) is the primary transcriptional regulator controlling the transcription of genes that code for Fe uptake and utilization proteins. Fpa (formerly YlaN) was demonstrated to be essential in Bacillus subtilis unless excess Fe is added to the growth medium, suggesting a role in Fe homeostasis. Here, we demonstrate that Fpa is essential in S. aureus upon Fe deprivation. Null fur alleles bypassed the essentiality of Fpa. The absence of Fpa abolished the derepression of Fur-regulated genes during Fe limitation. Bioinformatic analyses suggest that fpa was recruited to Gram-positive bacteria and, once acquired, was maintained in the genome as it co-evolved with Fur. Consistent with a role for Fpa in alleviating Fur-dependent repression, Fpa and Fur interacted in vivo, and Fpa decreased the DNA-binding ability of Fur in vitro. Fpa bound Fe(II) in vitro using oxygen or nitrogen ligands with an association constant that is consistent with a physiological role in Fe homeostasis. These findings have led to a model wherein Fpa is an Fe(II) binding protein that influences Fur-dependent regulation through direct interaction.IMPORTANCEIron (Fe) is an essential nutrient for nearly all organisms. If Fe homeostasis is not maintained, Fe may accumulate in the cytosol, which can be toxic. Questions remain about how cells efficiently balance Fe uptake and usage to prevent overload. Iron uptake and proper metalation of proteins are essential processes in the mammalian bacterial pathogen Staphylococcus aureus. Understanding the gene products involved in the genetic regulation of Fe uptake and usage and the physiological adaptations that S. aureus uses to survive in Fe-depleted conditions provides insight into pathogenesis. Herein, we demonstrate that the DNA-binding activity of the ferric uptake regulator transcriptional repressor is alleviated under Fe limitation, but uniquely, in S. aureus, alleviation requires the presence of Fpa.

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Fpa(YlaN)是一种铁(II)结合蛋白,其功能是缓解金黄色葡萄球菌中由呋喃介导的基因表达抑制。
铁(Fe)是几乎所有生物都需要的微量营养元素。由于对铁的需求以及非螯合的细胞膜离子铁的毒性,调控系统已经进化到可以在铁的获取和使用之间取得紧密平衡,同时限制过载。在包括哺乳动物病原体金黄色葡萄球菌在内的大多数细菌中,铁吸收调节因子(Fur)是控制铁吸收和利用蛋白编码基因转录的主要转录调节因子。除非在生长培养基中添加过量的铁,否则 Fpa(原 YlaN)在枯草芽孢杆菌中是必不可少的,这表明它在铁平衡中发挥作用。在这里,我们证明了 Fpa 在金黄色葡萄球菌缺铁时是必不可少的。裘皮等位基因的缺失绕过了 Fpa 的必要性。Fpa的缺失会导致铁限制过程中Fur调控基因的抑制作用减弱。生物信息学分析表明,Fpa被招募到革兰氏阳性细菌中,一旦获得,就会在基因组中与Fur共同进化。与 Fpa 在减轻 Fur 依赖性抑制中的作用相一致,Fpa 和 Fur 在体内相互作用,Fpa 在体外降低了 Fur 的 DNA 结合能力。在体外,Fpa 利用氧或氮配体与铁(II)结合,其结合常数与在铁平衡中的生理作用一致。这些发现建立了一个模型,其中 Fpa 是一种铁(II)结合蛋白,它通过直接相互作用影响 Fur 依赖性调控。重要意义铁(Fe)是几乎所有生物的必需营养素。如果不能维持铁的平衡,铁就会在细胞质中积累,从而产生毒性。细胞如何有效地平衡铁的摄取和使用以防止过载仍是一个问题。铁的吸收和蛋白质的适当金属化是哺乳动物细菌病原体金黄色葡萄球菌的基本过程。了解参与铁吸收和利用遗传调控的基因产物,以及金黄色葡萄球菌在缺铁条件下生存的生理适应,有助于深入了解致病机理。在这里,我们证明了铁吸收调节转录抑制因子的 DNA 结合活性在铁限制条件下会得到缓解,但独特的是,在金黄色葡萄球菌中,缓解需要 Fpa 的存在。
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来源期刊
mBio
mBio MICROBIOLOGY-
CiteScore
10.50
自引率
3.10%
发文量
762
审稿时长
1 months
期刊介绍: mBio® is ASM''s first broad-scope, online-only, open access journal. mBio offers streamlined review and publication of the best research in microbiology and allied fields.
期刊最新文献
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