Pleiotropic Effects of the P5-Type ATPase SpfA on Stress Response Networks Contribute to Virulence in the Pathogenic Mold Aspergillus fumigatus.
Pleiotropic Effects of the P5-Type ATPase SpfA on Stress Response Networks Contribute to Virulence in the Pathogenic Mold Aspergillus fumigatus.
复制标题
P5型ATPase SPFA对应力反应网络的多效性作用有助于致病性霉菌曲霉的毒力。
DOI：
10.1128/mbio.02735-21
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发表时间：
2021-10-26
期刊：
影响因子：
6.4
通讯作者：
Askew DS
中科院分区：
文献类型：
--
作者：
Guirao-Abad JP;Weichert M;Luengo-Gil G;Sze Wah Wong S;Aimanianda V;Grisham C;Malev N;Reddy S;Woollett L;Askew DS
烟曲霉是一种人类致病真菌，通过分泌水解酶从环境或宿主组织中提取营养物质。A.烟曲霉调节分泌水平与需求成比例依赖于未折叠蛋白反应（UPR）的辅助，UPR是调节内质网（ER）的独特蛋白折叠环境的适应性应激反应途径。P5型ATP酶Spf 1最近被认为参与了一种新的ER稳态机制，该机制涉及纠正ER膜蛋白靶向的错误。然而，该蛋白对A.烟曲霉是未知的。在这里，我们采用基因敲除和RNA测序策略来确定A.烟曲霉基因编码正磷酸酶P5 ATP酶SpfA。这些数据表明，spfA基因诱导ER压力在一个UPR依赖的方式。在没有spfA的情况下，A.烟曲霉转录组向改变的氧化还原和脂质平衡的概况转变，除了ER应激的特征，包括srcA，编码ER中的第二个P型ATP酶。ΔspfA缺失突变体对ER应激、氧化应激和靶向细胞壁或质膜的抗真菌药物的敏感性增加。在两种动物感染模型中，spfA和srcA的联合缺失加剧了这些表型并减弱了毒力。这些研究结果表明，ER-居民ATP酶SpfA和SrcA的共同行动，以支持不同的适应功能的ER是必要的健身在宿主环境中。
Aspergillus fumigatus is a human-pathogenic mold that extracts nutrients from the environment or from host tissues by secreting hydrolytic enzymes. The ability of A. fumigatus to adjust secretion levels in proportion to demand relies on the assistance of the unfolded protein response (UPR), an adaptive stress response pathway that regulates the unique protein-folding environment of the endoplasmic reticulum (ER). The P5-type ATPase Spf1 has recently been implicated in a novel mechanism of ER homeostasis that involves correcting errors in ER-membrane protein targeting. However, the contribution of this protein to the biology of A. fumigatus is unknown. Here, we employed a gene knockout and RNA sequencing strategy to determine the functional role of the A. fumigatus gene coding for the orthologous P5 ATPase SpfA. The data reveal that the spfA gene is induced by ER stress in a UPR-dependent manner. In the absence of spfA, the A. fumigatus transcriptome shifts toward a profile of altered redox and lipid balance, in addition to a signature of ER stress that includes srcA, encoding a second P-type ATPase in the ER. A ΔspfA deletion mutant showed increased sensitivity to ER stress, oxidative stress, and antifungal drugs that target the cell wall or plasma membrane. The combined loss of spfA and srcA exacerbated these phenotypes and attenuated virulence in two animal infection models. These findings demonstrate that the ER-resident ATPases SpfA and SrcA act jointly to support diverse adaptive functions of the ER that are necessary for fitness in the host environment.