COMPARING THE HSP90 GENETIC INTERACTION NETWORK LANDSCAPE GOVERNING FUNGAL LIFE

比较控制真菌生命的 HSP90 遗传相互作用网络景观

• 批准号: BB/L007886/1
• 负责人: Stephanie Diezmann
• 金额: $ 54.53万
• 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=BB%2FL007886%2F1
• 关键词: COMPARING; HSP90; GENETIC; INTERACTION; NETWORK

Sex is important for it permits reshuffling of genes and this process of reshuffling aids in adaptation to new environmental conditions. But what do organisms do that do not have sex? How do they face environmental challenges, such as high temperatures?We will address these questions by focusing on a special protein called heat shock protein Hsp90. As its name implies, it is important during heat stress. Hence, every organism from bacteria to humans requires it for life. Hsp90 stabilizes other proteins that are involved in such crucial processes as cell division, development and stress response. Two specific examples of how Hsp90 affects life include its chaperoning of proteins involved in human cancers and the emergence of drug resistance in fungi. Indeed, Hsp90 interacts with and stabilizes up to 10% of all other proteins in the cell. This organization, which includes Hsp90 and its interactors, is called the Hsp90 chaperone network. We hypothesize that the network and its interactors are changing over evolutionary time depending on the environmental conditions. This helps organisms, such as asexual fungi, adapt to new environments. Since Hsp90 occupies a central position in regulating gene function, addressing these questions will inform our understanding about some important basic biological mechanisms.Fungi are excellent model organisms to test this hypothesis. We will employ three different fungi that diverged about half a billion years ago and live in very different environments. One occupies fruits. Another lives in pigeon guano and trees but can cause severe infections of the human brain in AIDS patients. The third fungus lives naturally in the mouth and guts of humans but can cause life-threatening infections under special circumstances. Only the first fungus is capable of exchanging genetic material, the other two are not. Due to their diverse life styles and modes of exchanging genes, these three fungi have been developed as model systems over the past decades. In fact, the experimental tools required to map the Hsp90 chaperone network to date only exist in these fungi.We will investigate how the Hsp90 chaperone network aids organisms in the exploration of novel environments without the benefits of sex by pursuing three objectives. First, we will map the Hsp90 chaperone networks in the three fungi when grown in six different environmental conditions. Second, we will collaborate with mathematicians to analyze which kinds of proteins are particularly common in our networks and test conditions. Third, we will study how specific Hsp90 interactors affect fungal stress responses.Our research program will deliver three new chaperone network maps. By comparing them with each other, we will understand how networks change over time and in dependence of different environmental conditions. We will, furthermore identify novel Hsp90 interactors and understand how specific interactors affect stress adaptation in different fungi.The research proposed here will benefit a diverse clientele. In the short-term, on a scholarly level, we will be able to assess the impact of the Hsp90 chaperone network on an organism's ability to colonize new spaces. We will identify novel interactors that can be further investigated by scientists interested in the diverse aspects of Hsp90 biology, including geneticists, cancer biologists, and fungi researchers. We will provide theoretical biologists with network data that they can use to generate new hypothesis, which in turn can then be tested by biologists. The long-term beneficiaries of our research will be patients in the UK and world-wide who suffer from cancer and fungal infections, both of which are regulated by Hsp90. Our novel Hsp90 interactors could potentially lead to the development of new drugs to help conquer cancer and fight fungal infections.

性很重要，因为它允许基因重组，而这种重组过程有助于适应新的环境条件。但是没有性行为的生物体会做什么呢？它们如何面对高温等环境挑战？我们将通过关注一种称为热休克蛋白 Hsp90 的特殊蛋白质来解决这些问题。顾名思义，它在热应激期间很重要。因此，从细菌到人类的每一种生物体的生命都需要它。 Hsp90 可以稳定参与细胞分裂、发育和应激反应等关键过程的其他蛋白质。 Hsp90 如何影响生命的两个具体例子包括它对与人类癌症有关的蛋白质的陪伴以及真菌中耐药性的出现。事实上，Hsp90 与细胞中高达 10% 的其他蛋白质相互作用并稳定其稳定性。该组织包括 Hsp90 及其相互作用者，称为 Hsp90 伴侣网络。我们假设网络及其交互者随着进化时间的变化而变化，具体取决于环境条件。这有助于无性真菌等生物体适应新环境。由于Hsp90在调节基因功能中占据核心地位，解决这些问题将有助于我们理解一些重要的基本生物学机制。真菌是检验这一假设的极好模型生物。我们将使用三种不同的真菌，它们大约在十亿年前分化并生活在非常不同的环境中。一者占据水果。另一种生活在鸽子粪便和树上，但可导致艾滋病患者的人脑严重感染。第三种真菌自然生活在人类的口腔和肠道中，但在特殊情况下可能会导致危及生命的感染。只有第一种真菌能够交换遗传物质，其他两种则不能。由于它们多样化的生活方式和基因交换模式，这三种真菌在过去几十年中已被开发为模型系统。事实上，迄今为止绘制 Hsp90 伴侣网络所需的实验工具仅存在于这些真菌中。我们将通过追求三个目标来研究 Hsp90 伴侣网络如何帮助生物体探索新的环境，而无需性的好处。首先，我们将绘制三种真菌在六种不同环境条件下生长时的 Hsp90 伴侣网络。其次，我们将与数学家合作，分析哪些类型的蛋白质在我们的网络和测试条件中特别常见。第三，我们将研究特定的 Hsp90 相互作用因子如何影响真菌应激反应。我们的研究计划将提供三个新的伴侣网络图。通过相互比较，我们将了解网络如何随着时间的推移以及不同环境条件的变化而变化。我们还将进一步鉴定新的 Hsp90 相互作用因子，并了解特定相互作用因子如何影响不同真菌的应激适应。此处提出的研究将使不同的客户受益。短期内，在学术层面上，我们将能够评估 Hsp90 伴侣网络对生物体殖民新空间的能力的影响。我们将鉴定新的相互作用因子，对 Hsp90 生物学各个方面感兴趣的科学家（包括遗传学家、癌症生物学家和真菌研究人员）可以进一步研究这些相互作用因子。我们将为理论生物学家提供网络数据，他们可以使用这些数据来生成新的假设，然后生物学家可以对其进行测试。我们研究的长期受益者将是英国和世界各地患有癌症和真菌感染的患者，这两种疾病都受到 Hsp90 的调节。我们的新型 Hsp90 相互作用因子可能会导致新药的开发，以帮助征服癌症和对抗真菌感染。

项目成果

Functional Divergence of Hsp90 Genetic Interactions in Biofilm and Planktonic Cellular States.

• DOI: 10.1371/journal.pone.0137947
• 发表时间: 2015
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Diezmann S;Leach MD;Cowen LE
• 通讯作者: Cowen LE

Hsp90 interaction networks in fungi-tools and techniques.

• DOI: 10.1093/femsyr/foab054
• 发表时间: 2021-11-16
• 期刊: FEMS yeast research
• 影响因子: 3.2
• 作者: Crunden JL;Diezmann S
• 通讯作者: Diezmann S

Mapping the Hsp90 Genetic Network Reveals Ergosterol Biosynthesis and Phosphatidylinositol-4-Kinase Signaling as Core Circuitry Governing Cellular Stress.

• DOI: 10.1371/journal.pgen.1006142
• 发表时间: 2016-06
• 期刊: PLoS genetics
• 影响因子: 4.5
• 作者: O'Meara TR;Veri AO;Polvi EJ;Li X;Valaei SF;Diezmann S;Cowen LE
• 通讯作者: Cowen LE