The fungal-specific subunit i/j of F1FO-ATP synthase stimulates the pathogenicity of Candida albicans independent of oxidative phosphorylation
The fungal-specific subunit i/j of F1FO-ATP synthase stimulates the pathogenicity of Candida albicans independent of oxidative phosphorylation
复制标题
F1FO-ATP 合酶的真菌特异性亚基 i/j 刺激白色念珠菌的致病性，与氧化磷酸化无关
DOI：
10.1093/mmy/myaa094
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Hong Zhang
中科院分区：
文献类型：
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作者：
Yajing Zhao;Yan Lyu;Yanli Zhang;Shuixiu Li;Yishan Zhang;Yuting Liu;Chuanyan Tang;Zhanpeng Zhang;Dongmei Li;Hong Zhang
侵袭性真菌感染是人类死亡的主要原因，部分原因是由于非常有限的抗真菌药物库。真菌特异性致病机制的鉴定被认为是当前抗真菌药物开发的关键步骤，并且代表了提高功效和降低宿主毒性的重要目标。尽管F1 FO-ATP合酶的整体结构在真菌和哺乳动物中很大程度上是保守的，但亚基i/j（Su i/j，Atp 18）和亚基k（Su k，Atp 19）是在哺乳动物中未发现的并且对真菌特异的蛋白质。在此，Su i/j和Su k在白色念珠菌中的作用通过体内毒力评估和体外生长和线粒体功能来表征。引人注目的是，theatp 18 Δ/Δ突变体在系统性小鼠模型中显示出显著降低的致病性。然而，这种感染性的实质性缺陷存在于线粒体氧化磷酸化或体外增殖的相关缺陷中。毒力相关性状的分析显示两种突变体均正常，但atp 18 Δ/Δ突变体的细胞壁在组成和结构上存在缺陷。我们还发现theatp 18 Δ/Δ突变体比野生型更容易受到巨噬细胞的攻击，这可能与细胞壁功能异常和对氧化应激的敏感性增加密切相关。相比之下，在这些研究中均未观察到theatp 19 Δ/Δ的显著变化。这些结果表明，真菌特异性的F1 FO-ATP合酶的Su i/j，而不是Su k，可能在C.本研究旨在探讨白念珠菌ATP合成酶亚基i/j和k的生物学功能。白色念珠菌氧化磷酸化和毒力潜力。我们的研究结果表明，亚基i/j，而不是亚基k，是C的关键。白念珠菌性
Invasive fungal infections are a major cause of human mortality due in part to a very limited antifungal drug arsenal. The identification of fungal-specific pathogenic mechanisms is considered a crucial step to current antifungal drug development and represents a significant goal to increase the efficacy and reduce host toxicity. Although the overall architecture of F1FO-ATP synthase is largely conserved in both fungi and mammals, the subunit i/j (Su i/j, Atp18) and subunit k (Su k, Atp19) are proteins not found in mammals and specific to fungi. Here, the role of Su i/j and Su k inCandida albicanswas characterized by anin vivoassessment of the virulence andin vitrogrowth and mitochondrial function. Strikingly, theatp18Δ/Δ mutant showed significantly reduced pathogenicity in systemic murine model. However, this substantial defect in infectivity exists without associated defects in mitochondrial oxidative phosphorylation or proliferationin vitro. Analysis of virulence-related traits reveals normal in both mutants, but shows cell wall defects in composition and architecture in the case ofatp18Δ/Δ. We also find that theatp18Δ/Δ mutant is more susceptible to attack by macrophages than wild type, which may correlate well with the abnormal cell wall function and increased sensitivity to oxidative stress. In contrast, no significant changes were observed in any of these studies for theatp19Δ/Δ. These results demonstrate that the fungal-specific Su i/j, but not Su k of F1FO-ATP synthase may play a critical role inC. albicansinfectivity and represent another opportunity for new therapeutic target investigation.Lay AbstractThis study aims to investigate biological functions of fungal-specific subunit i/j and subunit k of ATP synthase inC. albicansoxidative phosphorylation and virulence potential. Our results revealed that subunit i/j, and not subunit k, is critical forC. albicanspathogenicity.