Central role of Nrg1 in the niche-specific coordination of morphogenesis stress responses and metabolism in the fungal pathogen Candida albicans

Nrg1 在真菌病原体白色念珠菌形态发生应激反应和代谢的生态位特异性协调中的核心作用

• 批准号: BB/F000111/1
• 负责人: Al Brown
• 金额: $ 57.44万
• 依托单位: University of Aberdeen
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2007
• 资助国家: 英国
• 起止时间: 2007 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FF000111%2F1
• 关键词: Central; role; Nrg1; niche; specific

The fungus, Candida albicans is medically important because it causes a range of infections in humans, some of which can be lethal. It causes frequent infections of the mouth, especially in young babies, the aged and in AIDS patients. Also, most women suffer at least one 'thrush' infection during their lifetime. Candida also causes life-threatening 'systemic' infections in intensive care patients whose immunological defences are significantly weakened (e.g. in transplant and cancer patients). Considerable research efforts have been devoted to the question 'What makes Candida such a good pathogen?'. Many research groups have focussed their attention on virulence factors. These have been defined as fungal factors that interact directly with the human host to promote infection (i.e. enhance fungal pathogenicity). These virulence factors include the ability of this fungus to switch reversibly between a yeast-like growth form and a hyphal (mycelial) growth form, which is believed to help the fungus invade tissue. Candida switches to hyphal growth in response to specific environmental triggers, which include serum or glucose. This switch is controlled by a complex biological circuitry: some regulatory proteins activate hyphal development in response to these environmental triggers, whilst others repress hyphal development in the absence of these triggers. We have studied a key repressor in some detail - Nrg1. We have shown that Nrg1 is a regulatory protein that prevents hyphal growth in the absence of hypha-inducing environmental triggers. In the course of these studies we have found that, in addition to regulating hyphal development, Nrg1 controls the expression of genes involved in stress protection and carbon metabolism. This is highly significant because these processes are essential for the pathogenicity of Candida. (Human immune cells kill microbial invaders by exposing them to oxidizing chemicals. Candida must be able to protect itself from these oxidative stresses if it is to counteract these host defences successfully and establish an infection. Also, Candida must assimilate nutrients from the host to be able to grow and infect its host. This nutrient assimilation depends upon carbon metabolism.) Hence the regulator Nrg1 seems to be playing a vital role by coordinating a range of important cellular functions that are required for survival in the host (hyphal development, stress protection and metabolism). How does Nrg1 do this? The main objective of this project is to address this question. We have shown that the Nrg1 protein is chemically modified (phosphorylated) and that the level of phosphorylation changes during the yeast-to-hyphal switch. Our hypothesis is that accurate chemical modification is vital for the control of Nrg1 activity, and hence central to the ability of Candida to coordinate its hyphal development, stress protection and metabolism. In this project we will test this hypothesis using a powerful combination of the latest experimental tools. We will define which sites on Nrg1 are modified, identify which enzymes catalyse these modifications, and establish the effects of disrupting these modifications upon the pathogenicity of Candida. These studies will dramatically advance our understanding of how Candida pathogenicity is regulated at the molecular level.

真菌，白色念珠菌是医学上重要的，因为它会导致一系列人类感染，其中一些可能是致命的。它导致口腔经常感染，特别是在婴儿、老年人和艾滋病患者中。此外，大多数妇女在一生中至少遭受一次“鹅口疮”感染。念珠菌还可导致重症监护患者发生危及生命的“全身性”感染，这些患者的免疫防御能力显著减弱（例如，移植患者和癌症患者）。相当多的研究工作一直致力于这个问题“是什么使念珠菌这样一个好的病原体？'.许多研究小组将注意力集中在毒力因子上。这些已被定义为直接与人类宿主相互作用以促进感染（即增强真菌致病性）的真菌因子。这些毒力因子包括这种真菌在酵母样生长形式和菌丝（菌丝体）生长形式之间可逆地转换的能力，这被认为有助于真菌侵入组织。念珠菌切换到菌丝生长响应特定的环境触发器，其中包括血清或葡萄糖。这个开关是由一个复杂的生物电路控制：一些调节蛋白激活菌丝发育响应这些环境触发，而其他抑制菌丝发育在没有这些触发。我们已经详细研究了一个关键的阻遏物-Nrg 1。我们已经表明，Nrg 1是一种调节蛋白，防止菌丝生长的情况下，菌丝诱导的环境触发。在这些研究的过程中，我们发现，除了调节菌丝发育，Nrg 1控制参与胁迫保护和碳代谢的基因的表达。这是非常重要的，因为这些过程对于念珠菌的致病性至关重要。（人类免疫细胞通过暴露于氧化化学物质来杀死微生物入侵者。念珠菌必须能够保护自己免受这些氧化应激，如果它是成功地抵消这些宿主防御和建立感染。此外，念珠菌必须从宿主中吸收营养才能生长并感染宿主。这种营养吸收取决于碳代谢。因此，调节因子Nrg 1似乎通过协调宿主生存所需的一系列重要细胞功能（菌丝发育，应激保护和代谢）发挥着至关重要的作用。Nrg 1是如何做到这一点的？该项目的主要目标是解决这一问题。我们已经表明，Nrg 1蛋白是化学修饰（磷酸化）和磷酸化水平的变化，在酵母菌丝开关。我们的假设是，准确的化学修饰是至关重要的Nrg 1活性的控制，因此中央念珠菌协调其菌丝发育，应力保护和代谢的能力。在这个项目中，我们将使用最新的实验工具的强大组合来测试这个假设。我们将定义Nrg 1上的哪些位点被修饰，确定哪些酶催化这些修饰，并建立破坏这些修饰对念珠菌致病性的影响。这些研究将极大地推进我们对念珠菌致病性如何在分子水平上调节的理解。

项目成果

Nitrosative and oxidative stress responses in fungal pathogenicity.

• DOI: 10.1016/j.mib.2009.06.007
• 发表时间: 2009-08
• 期刊: CURRENT OPINION IN MICROBIOLOGY
• 影响因子: 5.4
• 作者: Brown, Alistair J. P.;Haynes, Ken;Quinn, Janet
• 通讯作者: Quinn, Janet

The evolutionary rewiring of ubiquitination targets has reprogrammed the regulation of carbon assimilation in the pathogenic yeast Candida albicans.

• DOI: 10.1128/mbio.00495-12
• 发表时间: 2012-12-11
• 期刊: mBio
• 影响因子: 6.4
• 作者: Sandai D;Yin Z;Selway L;Stead D;Walker J;Leach MD;Bohovych I;Ene IV;Kastora S;Budge S;Munro CA;Odds FC;Gow NA;Brown AJ
• 通讯作者: Brown AJ

Activation of the heat shock transcription factor Hsf1 is essential for the full virulence of the fungal pathogen Candida albicans.

• DOI: 10.1016/j.fgb.2010.08.010
• 发表时间: 2011-03
• 期刊: FUNGAL GENETICS AND BIOLOGY
• 影响因子: 3
• 作者: Nicholls, Susan;MacCallum, Donna M.;Kaffarnik, Florian A. R.;Selway, Laura;Peck, Scott C.;Brown, Alistair J. P.
• 通讯作者: Brown, Alistair J. P.

Stress adaptation in a pathogenic fungus.

• DOI: 10.1242/jeb.088930
• 发表时间: 2014-01-01
• 期刊: The Journal of experimental biology
• 作者: Brown AJ;Budge S;Kaloriti D;Tillmann A;Jacobsen MD;Yin Z;Ene IV;Bohovych I;Sandai D;Kastora S;Potrykus J;Ballou ER;Childers DS;Shahana S;Leach MD
• 通讯作者: Leach MD

MNL1 regulates weak acid-induced stress responses of the fungal pathogen Candida albicans.

• DOI: 10.1091/mbc.e07-09-0946
• 发表时间: 2008-10
• 期刊: Molecular biology of the cell
• 影响因子: 3.3
• 作者: M. Ramsdale;L. Selway;D. Stead;Janet Walker;Zhikang Yin;S. Nicholls;J. Crowe;E. Sheils;A. J. Brown