Deciphering the Candida albicans Hsp90 Kinase Interactome and Elucidating its Role in Fungal Virulence

破译白色念珠菌 Hsp90 激酶相互作用组并阐明其在真菌毒力中的作用

• 批准号: MR/L018349/1
• 负责人: Stephanie Diezmann
• 金额: $ 61.09万
• 依托单位: University of Bath
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FL018349%2F1
• 关键词: Deciphering; Candida; albicans; Hsp90; Kinase

This project aims to inform new treatments for Candida albicans, the leading fungal pathogen of humans. Aside from the common nonlethal infections, several hundred people die in the UK every year of bloodstream and organ infections caused by this yeast. It threatens patients whose immune defenses are already weakened from cancer chemotherapy, HIV/AIDS, surgery or by extremely low birth weight. Once Candida has spread through the bloodstream, it is extremely difficult to treat because it quickly develops resistance to currently available drugs. The emergence of drug resistances is facilitated by the heat shock protein 90 (Hsp90), which stabilizes other proteins, thus contributing to their activation.Hsp90 collaborates with Cdc37. Together they target signal transmitting proteins, so called kinases. The Hsp90/Cdc37 complex and its target kinases play an important role in the normal physiology of all cells. Sometimes though, Hsp90 goes astray. For example when it stabilizes cancer proteins in humans and promotes drug resistance in yeast. Both examples suggest that reducing Hsp90 may help fight cancer and yeast infections. Indeed, drugs reducing Hsp90 function are currently tested as anti-cancer drugs. Unfortunately though, human and yeast Hsp90 are very similar. This means, it is very difficult to reduce only yeast Hsp90 but not human Hsp90 to cure a life-threatening yeast infection. Animal models showed that reducing yeast Hsp90 in combination with drugs treating the yeast infection itself caused severe side effects.We will address this problem by investigating the role of Hsp90/Cdc37 and their associated kinases in yeast to understand how they contribute to the yeast's ability to cause life-threatening infections. Specifically, we aim to further advance our understanding of those kinases that are unique to yeast and that depend on Hsp90 as future drug targets. Targeting yeast specific components with a drug should prevent or at least drastically reduce side effects in patients.We previously showed that reducing Hsp90 in yeast cells that also lack one kinase causes yeast cell death. This could be a promising approach for the development of new drugs and treatment strategies. Especially since Hsp90 reducing drugs are already in clinical trial as anti-cancer drugs. We furthermore demonstrated that some kinases regulate Hsp90 and Cdc37, while many others depend on the Hsp90/Cdc37 for stability and activation. Yet, knowledge of the Hsp90/Cdc37 kinase signaling module is sparse in C. albicans.This project will examine the kinases that regulate the Hsp90/Cdc37 complex and the kinases that depend on Hsp90/Cdc37 by conducting three sets of experiments. First, we will determine how specific kinases regulate Hsp90 and Cdc37 and which parts of Hsp90/Cdc37 are indeed necessary for yeasts to cause disease. Second, we will focus on yeast specific kinases and study their role in yeast infections to understand, which is the most important kinase that would make the best drug target. Third, we will search the yeast genome for more kinases that depend on Hsp90 to widen the field of potential drug targets.Scientists and patients will benefit from our research. In the short-term, biologists will be able to translate our knowledge of the Hsp90/Cdc37 kinase circuitry to the disease-causing mechanisms they study in other fungi or microbes. Structural biologists could crystallize promising kinases to elucidate their structure, which is a prerequisite for drug development by pharmacologists. Since Hsp90 plays an important role in a number of biological processes, our results could be used by scientists investigating genetics, cancer biology, and microbiology. The long-term beneficiaries of our research will be patients in the UK and world-wide that suffer from yeast infections as our research could potentially lead to the development of new drugs to conquer life-threatening yeast infections.

该项目旨在为人类主要真菌病原体白色念珠菌提供新的治疗方法。除了常见的非致命性感染外，英国每年有数百人死于这种酵母引起的血液和器官感染。它威胁着那些免疫防御已经因癌症化疗、艾滋病毒/艾滋病、手术或极低出生体重而减弱的患者。一旦念珠菌通过血液传播，就很难治疗，因为它很快就会对目前可用的药物产生耐药性。耐药性的出现是由热休克蛋白90（Hsp 90）促进的，热休克蛋白90稳定其他蛋白质，从而有助于它们的激活。它们一起靶向信号传递蛋白，即所谓的激酶。Hsp 90/Cdc 37复合物及其靶激酶在所有细胞的正常生理中起重要作用。但有时候，HSP 90会迷路。例如，当它稳定人类的癌症蛋白质和促进酵母的耐药性时。这两个例子都表明，减少Hsp 90可能有助于对抗癌症和酵母菌感染。事实上，降低Hsp 90功能的药物目前正在作为抗癌药物进行测试。然而，人类和酵母Hsp 90非常相似。这意味着，仅减少酵母Hsp 90而不减少人Hsp 90来治愈危及生命的酵母感染是非常困难的。动物模型表明，减少酵母Hsp 90与治疗酵母感染本身的药物结合会引起严重的副作用。我们将通过研究酵母中Hsp 90/Cdc 37及其相关激酶的作用来解决这个问题，以了解它们如何有助于酵母导致危及生命的感染的能力。具体来说，我们的目标是进一步推进我们对酵母特有的激酶的理解，这些激酶依赖于Hsp 90作为未来的药物靶点。针对酵母特异性成分的药物应该可以预防或至少大大减少患者的副作用。我们以前的研究表明，减少酵母细胞中也缺乏一种激酶的Hsp 90会导致酵母细胞死亡。这可能是开发新药和治疗策略的一种有前途的方法。特别是因为减少Hsp 90的药物已经作为抗癌药物在临床试验中。我们进一步证明，一些激酶调节Hsp 90和Cdc 37，而许多其他激酶依赖于Hsp 90/Cdc 37的稳定性和激活。然而，C中对Hsp 90/Cdc 37激酶信号传导模块的了解却很少。本课题通过三组实验对调节Hsp 90/Cdc 37复合体的激酶和依赖于Hsp 90/Cdc 37的激酶进行研究。首先，我们将确定特定激酶如何调节Hsp 90和Cdc 37，以及Hsp 90/Cdc 37的哪些部分确实是酵母致病所必需的。其次，我们将重点关注酵母特异性激酶，并研究它们在酵母感染中的作用，以了解哪种激酶是最重要的激酶，可以成为最好的药物靶点。第三，我们将在酵母基因组中寻找更多依赖于Hsp 90的激酶，以拓宽潜在的药物靶点，科学家和患者将从我们的研究中受益。在短期内，生物学家将能够将我们对Hsp 90/Cdc 37激酶电路的了解转化为他们在其他真菌或微生物中研究的致病机制。结构生物学家可以结晶有前途的激酶，以阐明其结构，这是一个先决条件，药物开发的药理学家。由于Hsp 90在许多生物学过程中起着重要作用，我们的研究结果可供研究遗传学、癌症生物学和微生物学的科学家使用。我们的研究的长期受益者将是英国和世界各地患有酵母菌感染的患者，因为我们的研究可能会导致新药的开发，以征服危及生命的酵母菌感染。

项目成果

Identification and Phenotypic Characterization of Hsp90 Phosphorylation Sites That Modulate Virulence Traits in the Major Human Fungal Pathogen Candida albicans.

• DOI: 10.3389/fcimb.2021.637836
• 发表时间: 2021
• 期刊: Frontiers in cellular and infection microbiology
• 影响因子: 5.7
• 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
• 通讯作者: Diezmann S