Gahlawat Abhilasha, Bhattacharyya Sunanda, Bhattacharyya Mrinal Kanti
Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, India.
Department of Biotechnology and Bioinformatics, School of Life Sciences, University of Hyderabad, Hyderabad, India.
mSphere. 2025 Sep 24:e0032925. doi: 10.1128/msphere.00329-25.
Hsp90 is considered to be the master regulator of chaperone activity within the cellular context. In addition to aiding client maturation and maintaining protein homeostasis, Hsp90 serves various non-canonical functions in model eukaryotes: ranging from protein-trafficking into the nucleus to transcriptional regulation, from chromatin remodeling to assembly and disassembly of protein complexes during DNA repair and telomere maintenance. In performing all these trades, Hsp90 collaborates with its co-chaperones in a client-specific or function-specific manner. Hsp90 undergoes various conformational changes during its chaperone cycle, which is regulated via several post-translational modifications (PTM). Different combinations of such PTMs, known as the chaperone code, also play key regulatory roles for Hsp90 functions. Here, we examine various cellular functions of Hsp90 in protozoan parasites, particularly those that shuttle between insect host and human host, adapting to a temperature difference of at least 10°C. Our analyses reveal that most of the prominent co-chaperones are present in all these parasites, except for one that is essential in model eukaryotes. We reviewed the biochemical correlates of Hsp90 and its co-chaperone interactions and realized that the physiological significance of such interplay is largely unknown in the protozoan parasites. One striking observation is the lack of sequence conservation of the parasitic co-chaperones with their human counterparts, making them attractive drug targets. Our analyses revealed that in spite of the identification of few PTMs of parasitic Hsp90 proteins, the chaperone codes remain largely elusive.IMPORTANCEHsp90 is a pivotal molecular chaperone involved in maintaining proteostasis and facilitating the maturation of diverse client proteins. Beyond its canonical folding functions, Hsp90 plays non-canonical roles in nuclear trafficking, transcriptional regulation, chromatin remodeling, and DNA repair. These activities are tightly regulated through interactions with specific co-chaperones and through post-translational modifications, collectively forming the "chaperone code." This study examines Hsp90's role in thermal adaptation of protozoan parasites when shuttling between the insect and human hosts. Here, we summarize the canonical and diverse non-canonical functions of Hsp90 in three protozoan parasites: , , and . We highlight all the Hsp90 isoforms found in these three parasites and also illustrate all the co-chaperones and post-translational modifications of Hsp90 found to be present in these protozoan parasites. Importantly, the divergence in co-chaperone sequences from human homologs in these parasites presents a promising avenue for targeted antiparasitic drug discovery and development.
Hsp90被认为是细胞环境中伴侣活性的主要调节因子。除了帮助客户蛋白成熟和维持蛋白质稳态外，Hsp90在模式真核生物中还发挥着各种非经典功能：从蛋白质转运到细胞核到转录调控，从染色质重塑到DNA修复和端粒维持过程中蛋白质复合物的组装和拆卸。在执行所有这些功能时，Hsp90以客户特异性或功能特异性的方式与其伴侣蛋白协同作用。Hsp90在其伴侣循环中经历各种构象变化，这是通过几种翻译后修饰（PTM）来调节的。这些PTM的不同组合，即所谓的伴侣密码，也对Hsp90的功能起着关键的调节作用。在这里，我们研究了Hsp90在原生动物寄生虫中的各种细胞功能，特别是那些在昆虫宿主和人类宿主之间穿梭、适应至少10°C温差的寄生虫。我们的分析表明，除了一种在模式真核生物中必不可少的伴侣蛋白外，大多数重要的伴侣蛋白在所有这些寄生虫中都存在。我们回顾了Hsp90及其伴侣蛋白相互作用的生化相关性，意识到这种相互作用的生理意义在原生动物寄生虫中基本上是未知的。一个显著的观察结果是，寄生虫伴侣蛋白与其人类对应物缺乏序列保守性，这使它们成为有吸引力的药物靶点。我们的分析表明，尽管已经鉴定出了少数寄生虫Hsp90蛋白的PTM，但伴侣密码在很大程度上仍然难以捉摸。
Hsp90是一种关键的分子伴侣，参与维持蛋白质稳态并促进各种客户蛋白的成熟。除了其经典的折叠功能外，Hsp90在核转运、转录调控、染色质重塑和DNA修复中发挥非经典作用。这些活动通过与特定伴侣蛋白的相互作用和翻译后修饰受到严格调控，共同形成了“伴侣密码”。本研究探讨了Hsp90在原生动物寄生虫在昆虫和人类宿主之间穿梭时的热适应中的作用。在这里，我们总结了Hsp90在三种原生动物寄生虫（，和）中的经典和多样的非经典功能。我们突出了在这三种寄生虫中发现的所有Hsp90异构体，并说明了在这些原生动物寄生虫中发现的Hsp90的所有伴侣蛋白和翻译后修饰。重要的是，这些寄生虫中伴侣蛋白序列与人类同源物的差异为靶向抗寄生虫药物的发现和开发提供了一条有希望的途径。
