Identification and Phenotypic Characterization of Hsp90 Phosphorylation Sites That Modulate Virulence Traits in the Major Human Fungal Pathogen Candida albicans.
Identification and Phenotypic Characterization of Hsp90 Phosphorylation Sites That Modulate Virulence Traits in the Major Human Fungal Pathogen Candida albicans.
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DOI：
10.3389/fcimb.2021.637836
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发表时间：
2021
影响因子：
5.7
通讯作者：
Diezmann S
中科院分区：
文献类型：
--
作者：
Alaalm L;Crunden JL;Butcher M;Obst U;Whealy R;Williamson CE;O'Brien HE;Schaffitzel C;Ramage G;Spencer J;Diezmann S
高度保守、普遍存在的分子伴侣Hsp90是细胞蛋白酶抑制和环境应激反应的关键调节因子。在人类致病性真菌中，Hsp90控制着细胞形态发生、耐药性和毒力，每年全世界有160多万患者死于这种真菌。然而，我们对真菌Hsp90功能的调控机制的理解仍然很少。翻译后修饰是自然界工具箱中调节蛋白质丰度和功能的强大组件。磷酸化在许多细胞信号通路中起着至关重要的作用，错误的磷酸化会对细胞产生可怕的后果。在Hsp90的情况下，磷酸化影响其稳定性并控制其与共同伴侣和客户的相互作用。从而调节细胞应对环境压力的能力。白色念珠菌是主要的人类真菌病原体之一，在全世界造成约75万例危及生命的侵袭性感染，死亡率高得令人无法接受。然而，目前尚不清楚Hsp90磷酸化是否以及如何影响白色念珠菌的毒力特征。在这里，我们发现Hsp90的磷酸化对毒力性状的表达至关重要。我们结合蛋白质组学、分子进化分析、结构建模和分子生物学来表征Hsp90磷酸化在这种非模型病原体中的作用。我们证明了磷酸化对关键的毒力性状，如热应激反应、形态发生和药物敏感性产生负面影响。我们的结果提供了一个特定的Hsp90磷酸化位点作为真菌毒力调节剂的第一个记录。Hsp90的翻译后修饰在未来的抗真菌药物靶点开发中具有重要价值。
The highly conserved, ubiquitous molecular chaperone Hsp90 is a key regulator of cellular proteostasis and environmental stress responses. In human pathogenic fungi, which kill more than 1.6 million patients each year worldwide, Hsp90 governs cellular morphogenesis, drug resistance, and virulence. Yet, our understanding of the regulatory mechanisms governing fungal Hsp90 function remains sparse. Post-translational modifications are powerful components of nature’s toolbox to regulate protein abundance and function. Phosphorylation in particular is critical in many cellular signaling pathways and errant phosphorylation can have dire consequences for the cell. In the case of Hsp90, phosphorylation affects its stability and governs its interactions with co-chaperones and clients. Thereby modulating the cell’s ability to cope with environmental stress. Candida albicans, one of the leading human fungal pathogens, causes ~750,000 life-threatening invasive infections worldwide with unacceptably high mortality rates. Yet, it remains unknown if and how Hsp90 phosphorylation affects C. albicans virulence traits. Here, we show that phosphorylation of Hsp90 is critical for expression of virulence traits. We combined proteomics, molecular evolution analyses and structural modeling with molecular biology to characterize the role of Hsp90 phosphorylation in this non-model pathogen. We demonstrated that phosphorylation negatively affects key virulence traits, such as the thermal stress response, morphogenesis, and drug susceptibility. Our results provide the first record of a specific Hsp90 phosphorylation site acting as modulator of fungal virulence. Post-translational modifications of Hsp90 could prove valuable in future exploitations as antifungal drug targets.