Vam6/Vps39/ trap1结构域蛋白影响新生隐球菌液泡形态、铁获取和毒力

IF 2.6 2区 生物学 Q3 CELL BIOLOGY
Guanggan Hu, Erik Bakkeren, Mélissa Caza, Linda Horianopoulos, Eddy Sánchez-León, Melanie Sorensen, Wonhee Jung, James W. Kronstad
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引用次数: 2

摘要

致病性新隐球菌必须克服铁的限制才能在哺乳动物宿主中引起疾病。以前,我们报道了一个筛选插入突变体与生长不良的血红素作为唯一的铁源。在这项研究中,我们描述了一个这样的突变,发现缺陷基因编码了一个Vam6/Vps39/TRAP1结构域蛋白,这是血红素(宿主组织中重要的铁源)健壮生长所必需的。基于与酿酒酵母中相应蛋白的互易最佳匹配,我们将该蛋白命名为Vps3。C. neoformans编码第二种Vam6/Vps39/TRAP1结构域蛋白Vam6/Vlp1,我们发现该蛋白也是血红素和无机铁源上强劲生长所必需的。该蛋白被预测为参与内吞作用的同型融合和液泡蛋白分选复合体的一个组成部分。对vam6Δ和vps3Δ突变体的进一步表征显示,铁获取功能(例如,高亲和铁渗透酶Cft1)的运输受到干扰,转录因子Rim101(血红素和铁获取的调节因子)的加工受损。vps3Δ和vam6Δ突变体也具有多效性表型,包括隐球菌小鼠模型中的毒力丧失、毒力因子细化减少和对应激的易感性增加,这表明Vps3和Vam6在新生隐球菌中除了血红素外还具有多效性作用。两个Vam6/Vps39/ trap1结构域蛋白Vps3和Vam6支持新生隐球菌在血红素上的生长。Vps3和Vam6的缺失影响铁摄取蛋白的转运和表达。在隐球菌病小鼠模型中,Vps3或Vam6的缺失消除了新生隐球菌引起疾病的能力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Vam6/Vps39/TRAP1-domain proteins influence vacuolar morphology, iron acquisition and virulence in Cryptococcus neoformans

Vam6/Vps39/TRAP1-domain proteins influence vacuolar morphology, iron acquisition and virulence in Cryptococcus neoformans

The pathogenic fungus Cryptococcus neoformans must overcome iron limitation to cause disease in mammalian hosts. Previously, we reported a screen for insertion mutants with poor growth on haem as the sole iron source. In this study, we characterised one such mutant and found that the defective gene encoded a Vam6/Vps39/TRAP1 domain-containing protein required for robust growth on haem, an important iron source in host tissue. We designated this protein Vps3 based on reciprocal best matches with the corresponding protein in Saccharomyces cerevisiae. C. neoformans encodes a second Vam6/Vps39/TRAP1 domain-containing protein designated Vam6/Vlp1, and we found that this protein is also required for robust growth on haem as well as on inorganic iron sources. This protein is predicted to be a component of the homotypic fusion and vacuole protein sorting complex involved in endocytosis. Further characterisation of the vam6Δ and vps3Δ mutants revealed perturbed trafficking of iron acquisition functions (e.g., the high affinity iron permease Cft1) and impaired processing of the transcription factor Rim101, a regulator of haem and iron acquisition. The vps3Δ and vam6Δ mutants also had pleiotropic phenotypes including loss of virulence in a mouse model of cryptococcosis, reduced virulence factor elaboration and increased susceptibility to stress, indicating pleiotropic roles for Vps3 and Vam6 beyond haem use in C. neoformans.

Take Aways

  • Two Vam6/Vps39/TRAP1-domain proteins, Vps3 and Vam6, support the growth of Cryptococcus neoformans on haem.
  • Loss of Vps3 and Vam6 influences the trafficking and expression of iron uptake proteins.
  • Loss of Vps3 or Vam6 eliminates the ability of C. neoformans to cause disease in a mouse model of cryptococcosis.
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来源期刊
Cellular Microbiology
Cellular Microbiology 生物-微生物学
CiteScore
9.70
自引率
0.00%
发文量
26
审稿时长
3 months
期刊介绍: Cellular Microbiology aims to publish outstanding contributions to the understanding of interactions between microbes, prokaryotes and eukaryotes, and their host in the context of pathogenic or mutualistic relationships, including co-infections and microbiota. We welcome studies on single cells, animals and plants, and encourage the use of model hosts and organoid cultures. Submission on cell and molecular biological aspects of microbes, such as their intracellular organization or the establishment and maintenance of their architecture in relation to virulence and pathogenicity are also encouraged. Contributions must provide mechanistic insights supported by quantitative data obtained through imaging, cellular, biochemical, structural or genetic approaches.
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