Characterization of a conserved structural and functional module in Phytophthora effectors

疫霉效应子中保守结构和功能模块的表征

• 批准号: BB/W016788/1
• 负责人: Wenbo Ma
• 金额: $ 61.84万
• 依托单位: University of East Anglia
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FW016788%2F1
• 关键词: Characterization; conserved; structural; functional; module

Human population is projected to reach 9.7 billion by 2050. The looming challenge of feeding the rapidly growing population is threatened by crop losses from plant diseases. An average of 13% annual crop yield is lost to pathogens and pests. Developing crops with resistance to pathogens is a major mission in agriculture but it can only be accomplished after the establishment of a deep understanding of the governing principles in pathogenesis.Co-evolution is a central concept in host-pathogen interactions. Plants have evolved a myriad of defense mechanisms to prevent infection by potential pathogens, while pathogens employ effector proteins to overcome the immunity and cause disease. An important feature of effectors is their fast evolution. Pathogens often produce a diverse complement of effectors, reflecting constant arms race with their hosts. Understanding the molecular mechanisms that underlie effector evolution is critically important for designing innovative approaches to achieve sustainable resistance.In this project, we will focus on Phytophthora pathogens to investigate effector evolution. Phytophthora are filamentous eukaryotes that morphologically similar, but evolutionarily divergent, to fungi. All Phytophthora species are pathogens of plants; among them, the most notorious is Phytophthora infestans, which causes the potato late blight disease that triggered the Irish Famine. Remarkably, each Phytophthora species encodes hundreds to over one thousand effectors, many of which contain tandem repeats of a conserved structural module (called WY/LWY). It has been proposed that the WY/LWY tandem repeats facilitate the evolution of novel virulence activities, leading to diversification of the effector repertoire in Phytophthora. We aim to investigate how WY/LWY module contributes to the diversification of effector functions. For this purpose, we recently solved the crystal structure of a protein complex formed by a Phytophthora effector PSR2, which contains seven WY/LWY units, and the host Ser/Thr protein phosphatase PP2A. This interaction is mediated by a specific combination of two N-terminal WY/LWY units in PSR2 and required for the virulence activity of PSR2. Intriguingly, the same interaction interface is adopted by multiple LWY effectors on their N-terminal region; however, these effectors have different subcellular localizations in plant cells and contain diverse LWY units in their C-terminus. Based on these observations, we hypothesize that a subset of LWY effectors perform their virulence functions by hijacking the host PP2A phosphatase. We will investigate the mechanisms by which different PP2A-associating effectors recruit distinct sets of substrates to the PP2A enzyme for dephosphorylation and examine the role of PP2A as a novel susceptibility gene and a hub targeted by multiple pathogen effectors. This research will determine how the LWY serves as a functional module to enable diversification of the effectors. The outcome of this project will advance a fundamental understanding of Phytophthora pathogenesis and effector evolution. This knowledge will offer new opportunities to develop novel disease control strategies.

预计到2050年，人口将达到97亿。养活迅速增长的人口的挑战迫在眉睫，植物病害造成的作物损失威胁着这一挑战。每年平均有13%的作物产量因病原体和害虫而损失。培育具有抗病性的作物是农业的一项重要使命，但只有在对病原菌致病机理有了深刻的认识后才能实现。植物已经进化出无数的防御机制来防止潜在病原体的感染，而病原体则利用效应蛋白来克服免疫力并引起疾病。效应子的一个重要特征是它们的快速进化。病原体通常产生多种多样的效应子，反映了与宿主的持续军备竞赛。了解效应子进化的分子机制对于设计创新方法实现可持续抗性至关重要。在本项目中，我们将重点关注疫霉病原体，以研究效应子进化。疫霉属（Phytophthora）是丝状真核生物，形态上与真菌相似，但进化上与真菌不同。所有疫霉属物种都是植物的病原体;其中，最臭名昭著的是致病疫霉，它导致引发爱尔兰饥荒的马铃薯晚疫病。值得注意的是，每个疫霉属物种编码数百至超过一千个效应子，其中许多含有保守结构模块的串联重复序列（称为WY/LWY）。已经提出WY/LWY串联重复序列促进新的毒力活性的进化，导致疫霉属中效应子库的多样化。我们的目的是调查如何WY/LWY模块有助于多样化的效应功能。为此，我们最近解决了由疫霉属效应物PSR 2（其含有7个WY/LWY单位）和宿主Ser/Thr蛋白磷酸酶PP 2A形成的蛋白质复合物的晶体结构。这种相互作用由PSR 2中两个N-末端WY/LWY单位的特异性组合介导，并且是PSR 2的毒力活性所需的。有趣的是，多个LWY效应子在其N-末端区域上采用相同的相互作用界面;然而，这些效应子在植物细胞中具有不同的亚细胞定位，并且在其C-末端包含不同的LWY单元。基于这些观察结果，我们假设LWY效应子的一个子集通过劫持宿主PP 2A磷酸酶来执行其毒力功能。我们将调查的机制，不同的PP 2A相关效应招募不同的底物的PP 2A酶去磷酸化和检查PP 2A作为一种新的易感基因和多个病原体效应靶向枢纽的作用。这项研究将确定如何LWY作为一个功能模块，使多样化的效应器。该项目的结果将推进疫霉致病机理和效应子进化的基本理解。这些知识将为开发新的疾病控制策略提供新的机会。

项目成果

Pathogen protein modularity enables elaborate mimicry of a host phosphatase

• DOI: 10.1016/j.cell.2023.05.049
• 发表时间: 2023-06
• 期刊: Cell
• 影响因子: 64.5
• 作者: Hui Li;Jinlong Wang;T. Kuan;Bozeng Tang;Li Feng;Jiuyu Wang;Zhi Cheng;J. Skłenar;P. Derbyshire;Michelle T. Hulin;Yufei Li;Yi Zhai;Yingnan Hou;Frank L. H. Menke;Yanli Wang;Wenbo Ma