Candida albicans scavenges host zinc via Pra1 during endothelial invasion.
Candida albicans scavenges host zinc via Pra1 during endothelial invasion.
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DOI：
10.1371/journal.ppat.1002777
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发表时间：
2012
期刊：
影响因子：
6.7
通讯作者：
Wilson D
中科院分区：
文献类型：
--
作者：
Citiulo F;Jacobsen ID;Miramón P;Schild L;Brunke S;Zipfel P;Brock M;Hube B;Wilson D
病原微生物从其宿主中吸收必需营养的能力对于致病性至关重要。在这里，我们报告内皮锌螯合的主要人类真菌病原体，白色念珠菌。我们假设，类似于铁载体介导的铁获得，C。白色念珠菌利用细胞外锌清除剂来获取这种必需金属。我们推测，这样一个“锌载体”系统将包括一个分泌的因子与锌结合的特性，它可以特异性地与真菌细胞表面重新结合。对C.白念珠菌分泌蛋白组的锌结合基序鉴定的pH调节抗原1（Pra1）。Pra1的三维建模表明存在至少两个锌配位位点。事实上，重组表达的Pra1在体外表现出锌结合特性。C.白色念珠菌阻止真菌隔离和宿主锌的利用，并且在不存在外源锌的情况下特异性地阻断宿主细胞损伤。系统发育分析表明，PRA1出现在一个古老的真菌谱系和发展同线性ZRT1（编码锌转运蛋白）之前，分歧的子囊菌门和担子菌门。结构模型表明Pra1和Zrt1之间的物理相互作用，我们通过实验证实了这一点，证明Zrt1是必不可少的可溶性Pra1的细胞表面的结合。白色念珠菌因此，我们已经确定了一种新的金属收购系统组成的分泌锌清除剂（“zincophore”），它与真菌细胞重新关联。此外，功能相似性与遗传无关的原核系统表明，同线锌收购位点已独立选择在进化过程中。致病微生物从宿主那里获取营养的能力是感染的最基本方面之一。因此，宿主生物在一个称为营养免疫的过程中限制了微生物对某些关键营养素的获取。最近，人们发现，受感染的脊椎动物螯合锌从入侵的微生物控制感染。因此，微生物锌的获取机制代表了潜在的毒力属性。在这里，我们报告的分子机制，宿主来源的锌收购的主要人类真菌病原体，白色念珠菌。我们证明了C.白色念珠菌利用分泌的蛋白质，pH调节抗原1（Pra1），结合来自其环境的锌。然后Pra1通过一个同系编码的（遗传连锁的）膜转运蛋白（Zrt1）与真菌细胞重新结合，以获得这种必需的金属。PRA1的缺失阻止了宿主锌的利用和在不存在外源锌的情况下对宿主细胞的损伤。最后，我们证明，这个锌清除位点出现在一个古老的真菌谱系，并保持在许多当代物种的保守。同线排列的锌获取系统在真菌和细菌王国中独立进化，这表明这种排列对微生物的进化有益。
The ability of pathogenic microorganisms to assimilate essential nutrients from their hosts is critical for pathogenesis. Here we report endothelial zinc sequestration by the major human fungal pathogen, Candida albicans. We hypothesised that, analogous to siderophore-mediated iron acquisition, C. albicans utilises an extracellular zinc scavenger for acquiring this essential metal. We postulated that such a “zincophore” system would consist of a secreted factor with zinc-binding properties, which can specifically reassociate with the fungal cell surface. In silico analysis of the C. albicans secretome for proteins with zinc binding motifs identified the pH-regulated antigen 1 (Pra1). Three-dimensional modelling of Pra1 indicated the presence of at least two zinc coordination sites. Indeed, recombinantly expressed Pra1 exhibited zinc binding properties in vitro. Deletion of PRA1 in C. albicans prevented fungal sequestration and utilisation of host zinc, and specifically blocked host cell damage in the absence of exogenous zinc. Phylogenetic analysis revealed that PRA1 arose in an ancient fungal lineage and developed synteny with ZRT1 (encoding a zinc transporter) before divergence of the Ascomycota and Basidiomycota. Structural modelling indicated physical interaction between Pra1 and Zrt1 and we confirmed this experimentally by demonstrating that Zrt1 was essential for binding of soluble Pra1 to the cell surface of C. albicans. Therefore, we have identified a novel metal acquisition system consisting of a secreted zinc scavenger (“zincophore”), which reassociates with the fungal cell. Furthermore, functional similarities with phylogenetically unrelated prokaryotic systems indicate that syntenic zinc acquisition loci have been independently selected during evolution. The capacity of disease-causing microbes to acquire nutrients from their host is one of the most fundamental aspects of infection. Host organisms therefore restrict microbial access to certain key nutrients in a process known as nutritional immunity. Recently, it was found that infected vertebrates sequester zinc from invading microorganisms to control infection. Therefore, the mechanisms of microbial zinc acquisition represent potential virulence attributes. Here we report the molecular mechanism of host-derived zinc acquisition by the major human fungal pathogen, Candida albicans. We show that C. albicans utilises a secreted protein, the pH-regulated antigen 1 (Pra1), to bind zinc from its environment. Pra1 then reassociates with the fungal cell via a syntenically encoded (genetically-linked) membrane transporter (Zrt1) to acquire this essential metal. Deletion of PRA1 prevented utilisation of host zinc and damage of host cells in the absence of exogenous zinc. Finally, we demonstrate that this zinc-scavenging locus arose in an ancient fungal lineage and remains conserved in many contemporary species. Syntenically arranged zinc acquisition systems have evolved independently in the fungal and bacterial kingdoms, suggesting that such an arrangement is evolutionary beneficial for microorganisms.
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