HapX positively and negatively regulates the transcriptional response to iron deprivation in Cryptococcus neoformans.
HapX positively and negatively regulates the transcriptional response to iron deprivation in Cryptococcus neoformans.
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DOI：
10.1371/journal.ppat.1001209
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发表时间：
2010-11-24
期刊：
影响因子：
6.7
通讯作者：
Kronstad JW
中科院分区：
文献类型：
--
作者：
Jung WH;Saikia S;Hu G;Wang J;Fung CK;D'Souza C;White R;Kronstad JW
真菌病原体新型隐球菌是免疫功能低下个体（如艾滋病患者）患病的主要原因。真菌在宿主组织中增殖过程中获取营养的能力和制作多糖胶囊的能力是疾病结局的关键决定因素。我们之前的研究表明，GATA因子Cir1是宿主组织生长所需的铁摄取功能和关键毒力因子（如胶囊、黑色素和生长）在37°C下的主要调节因子。我们感兴趣的是进一步确定从无机和宿主来源的铁获取机制，以了解新形态芽孢杆菌对宿主环境的营养适应。在本研究中，我们研究了HAP3和HAPX基因在铁利用和毒力中的作用。与其他真菌一样，在低铁条件下，新形式C. Hap蛋白会对编码呼吸和TCA循环功能的基因表达产生负面影响。然而，我们也发现HapX在基因表达调控中既有正调控作用，也有负调控作用，其中对铁载体的表达有正调控作用。此外，HapX也正调控CIR1转录本的表达。这种情况与HapX对细粒曲霉和裂糖菌GATA铁调节因子编码基因的负调控形成对比。虽然hapX和hap3突变体在培养中血红素利用方面都存在缺陷，但只有hapX对毒力有贡献，在缺乏高亲和力铁摄取系统的菌株中，hapX的丢失不会导致疾病的进一步衰减。因此，在哺乳动物宿主感染过程中，HapX的作用似乎微乎其微，相反，它可能是环境铁摄取功能的重要调节因子。总的来说，这些结果表明新生C.在感染过程中采用多种铁获取策略。在免疫功能低下的人群中，如艾滋病患者，新型隐球菌会引起危及生命的中枢神经系统感染。新型C.等病原体与哺乳动物宿主之间对铁的竞争是疾病结果的一个关键方面。我们之前在C. neoformers中鉴定并表征了主要的铁调节蛋白Cir1，以及铁结合分子（铁载体）运输蛋白和高亲和力铁摄取蛋白。在这项研究中，我们研究了额外的调节蛋白（Hap蛋白）在低铁条件下的反应和宿主铁源（如血红素和转铁蛋白）的使用中的作用。我们发现HapX蛋白在缺铁过程中具有抑制铁依赖功能的保守调节功能，同时对铁载体转运蛋白的表达具有积极的调节作用。在培养中，hapX突变体在使用血红素作为铁源时存在缺陷，但在小鼠中的毒力仅轻微减弱。这一结果表明，必须有其他的铁摄取机制来支持新形态芽孢杆菌在宿主体内的增殖，并且HapX可能在环境铁获取中发挥重要作用。
The fungal pathogen Cryptococcus neoformans is a major cause of illness in immunocompromised individuals such as AIDS patients. The ability of the fungus to acquire nutrients during proliferation in host tissue and the ability to elaborate a polysaccharide capsule are critical determinants of disease outcome. We previously showed that the GATA factor, Cir1, is a major regulator both of the iron uptake functions needed for growth in host tissue and the key virulence factors such as capsule, melanin and growth at 37°C. We are interested in further defining the mechanisms of iron acquisition from inorganic and host-derived iron sources with the goal of understanding the nutritional adaptation of C. neoformans to the host environment. In this study, we investigated the roles of the HAP3 and HAPX genes in iron utilization and virulence. As in other fungi, the C. neoformans Hap proteins negatively influence the expression of genes encoding respiratory and TCA cycle functions under low-iron conditions. However, we also found that HapX plays both positive and negative roles in the regulation of gene expression, including a positive regulatory role in siderophore transporter expression. In addition, HapX also positively regulated the expression of the CIR1 transcript. This situation is in contrast to the negative regulation by HapX of genes encoding GATA iron regulatory factors in Aspergillus nidulans and Schizosaccharomyces pombe. Although both hapX and hap3 mutants were defective in heme utilization in culture, only HapX made a contribution to virulence, and loss of HapX in a strain lacking the high-affinity iron uptake system did not cause further attenuation of disease. Therefore, HapX appears to have a minimal role during infection of mammalian hosts and instead may be an important regulator of environmental iron uptake functions. Overall, these results indicated that C. neoformans employs multiple strategies for iron acquisition during infection. Cryptococcus neoformans causes life-threatening central nervous system infections in immunocompromised people such as AIDS patients. The competition for iron between pathogens such as C. neoformans and mammalian hosts is a key aspect of disease outcome. We previously identified and characterized the major iron regulatory protein Cir1 in C. neoformans, as well as proteins for the transport of iron-binding molecules (siderophores) and for high-affinity iron uptake. In this study, we examined the roles of additional regulatory proteins (Hap proteins) in the response to low-iron conditions and the use of host iron sources such as heme and transferrin. We discovered that the HapX protein has a conserved regulatory function to repress iron-dependent functions during iron deprivation, as well as a positive regulatory role for the expression of putative siderophore transporters. A hapX mutant was defective in the use of heme as an iron source in culture but was only modestly attenuated for virulence in mice. This result suggests that additional mechanisms for iron uptake must be available to support C. neoformans proliferation in the host, and that HapX may play an important role in environmental iron acquisition.
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