New approaches to undermine late blight disease by exploiting an understanding of ubiquitin E3 ligases that positively regulate immunity

利用对积极调节免疫的泛素 E3 连接酶的了解，开发出消灭晚疫病的新方法

基本信息

批准号：
BB/P020569/1
负责人：
Paul Birch
金额：
$ 50.37万
依托单位：
University of Dundee
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2017
资助国家：
英国
起止时间：
2017 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FP020569%2F1
关键词：
New approaches undermine late blight

项目摘要

An increasing world population and impacts of climate change place ever-greater demands on the world food supply. A major constraint to global food security is crop loss due to plant pests and diseases. With the increasing stringency of conditions under which chemicals are approved for agriculture, the choice of effective fungicides and pesticides will become more limited in the near future. There is an urgent need to explore the development of novel, durable and sustainable means to combat crop diseases. The development of such new approaches requires a deep understanding of the plant immune system, how it is regulated, and how pathogens are able to overcome it.Plants defend themselves with an inducible immune system. Immunity is activated by recognition of essential, widely conserved molecules (called PAMPs) that are exposed by pathogens during infection. Successful (adapted) pathogens secrete and deliver proteins called effectors to suppress these defences. Plant immunity involves a complex network of inter-linked signalling and regulatory processes. Regulation occurs at many levels, and a major component involves protein modification and turnover. A key protein modification that is emerging as a central regulator of plant immunity is ubiquitination, which often results in 26S proteasome-mediated degradation of ubiquitinated proteins. In the past decade we and others have revealed key enzymes, ubiquitin E3 ligases, which either positively or negatively regulate plant immunity. Considerable advances have been made to reveal the modes-of-action of E3 ligases that suppress immunity, by identifying their protein substrates for ubiquitination, marking them for proteasome-mediated degradation. E3 ligases that positively regulate immunity are less well understood and their substrates for ubiquitination are unknown. This proposal will address this critical knowledge gap.We will focus on 3 major E3 ligases that positively regulate immunity, CMPG1, PUB17 and UBK, two of which are targeted by effectors from the late blight pathogen Phytophthora infestans, emphasising their importance as central immune regulators that must be modified by this pathogen to suppress immunity. We provide crucial preliminary evidence that our methods and approaches reveal substrates of E3 ligases that activate immunity. Specifically, our preliminary work has revealed a KH RNA binding protein (KH17) which we show is a substrate for ubiquitination by PUB17, targeting it for degradation. We aim to extend this work to identify substrates of all three E3 ligases, which are predicted to be negative regulators of immunity. A specific outcome will be the identification of whether the substrates act as susceptibility [S] factors (i.e. are required for infection), as these provide targets to remove, by conditional silencing, to enhance immunity and provide disease resistance. A further aim is to investigate the roles of P. infestans effectors in inhibiting the E3 ligases. We will exploit this knowledge to generate mutant forms of two E3 ligases so that corresponding effectors can no longer inhibit their activity, thus restoring disease resistance.Remarkably, although ubiquitination has emerged as a central regulator of growth, development and immunity in plants, little is known about how it controls immunity. The identification and functional characterisation of E3 ligase substrates and regulators in governing immunity thereby provide a step-change in our understanding of how plant defence is controlled by this critical post-translational modification.

世界人口的增加和气候变化的影响对世界粮食供应提出了越来越高的要求。全球粮食安全的一个主要制约因素是植物病虫害造成的农作物损失。随着批准用于农业的化学品的条件越来越严格，在不久的将来，有效的杀菌剂和杀虫剂的选择将变得更加有限。迫切需要探索开发新颖、持久和可持续的手段来防治作物病害。此类新方法的开发需要深入了解植物免疫系统、其调节方式以及病原体如何克服它。植物通过诱导性免疫系统来保护自己。免疫是通过识别感染期间病原体暴露的重要的、广泛保守的分子（称为 PAMP）来激活的。成功的（适应的）病原体会分泌并传递称为效应子的蛋白质来抑制这些防御。植物免疫涉及一个由相互关联的信号传导和调节过程组成的复杂网络。调节发生在多个层面，其中一个主要部分涉及蛋白质修饰和周转。泛素化是一种正在成为植物免疫中央调节剂的关键蛋白质修饰，它通常会导致 26S 蛋白酶体介导的泛素化蛋白质降解。在过去的十年中，我们和其他人发现了关键酶，泛素 E3 连接酶，它可以积极或消极地调节植物免疫。通过鉴定E3连接酶泛素化的蛋白质底物，标记它们进行蛋白酶体介导的降解，揭示E3连接酶抑制免疫的作用模式已经取得了相当大的进展。对正向调节免疫的 E3 连接酶知之甚少，其泛素化底物也是未知的。该提案将解决这一关键的知识空白。我们将重点关注积极调节免疫的 3 种主要 E3 连接酶 CMPG1、PUB17 和 UBK，其中两种是晚疫病病原体致病疫霉效应子的靶标，强调它们作为中央免疫调节剂的重要性必须被这种病原体修饰以抑制免疫力。我们提供了重要的初步证据，证明我们的方法和途径揭示了激活免疫的 E3 连接酶的底物。具体来说，我们的初步工作揭示了一种 KH RNA 结合蛋白 (KH17)，我们证明它是 PUB17 泛素化的底物，从而靶向其降解。我们的目标是扩展这项工作以鉴定所有三种 E3 连接酶的底物，这些酶预计将成为免疫的负调节因子。具体结果将是确定底物是否充当易感性[S]因子（即感染所需），因为这些底物提供了通过条件沉默去除的目标，以增强免疫力并提供抗病性。进一步的目的是研究致病疫霉效应子在抑制 E3 连接酶中的作用。我们将利用这一知识来生成两种 E3 连接酶的突变形式，以便相应的效应子不再抑制其活性，从而恢复抗病性。值得注意的是，尽管泛素化已成为植物生长、发育和免疫的中心调节因子，但很少有研究发现泛素化已成为植物生长、发育和免疫的中心调节因子。了解它如何控制免疫力。因此，E3 连接酶底物和调控免疫调节因子的鉴定和功能表征使我们对植物防御如何通过这种关键的翻译后修饰进行控制的理解发生了重大变化。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Plant pathogen effector utilizes host susceptibility factor NRL1 to degrade the immune regulator SWAP70.

DOI：
10.1073/pnas.1808585115
发表时间：
2018-08-14
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
He Q;Naqvi S;McLellan H;Boevink PC;Champouret N;Hein I;Birch PRJ
通讯作者：
Birch PRJ

The Ubiquitin E3 Ligase PUB17 Positively Regulates Immunity by Targeting a Negative Regulator, KH17, for Degradation

DOI：
10.1016/j.xplc.2020.100020
发表时间：
2020-07-13
期刊：
PLANT COMMUNICATIONS
影响因子：
10.5
作者：
McLellan, Hazel;Chen, Kai;Birch, Paul R. J.
通讯作者：
Birch, Paul R. J.

A Phytophthora effector promotes homodimerization of host transcription factor StKNOX3 to enhance susceptibility.

疫霉效应子促进宿主转录因子 StKNOX3 的同二聚化以增强敏感性。

DOI：
10.1093/jxb/erac308
发表时间：
2022
期刊：
Journal of experimental botany
影响因子：
6.9
作者：
Zhou J
通讯作者：
Zhou J

Evolutionarily distinct Resistance proteins detect a pathogen effector through its association with different host targets.

DOI：
10.1111/nph.17660
发表时间：
2021-08
期刊：
The New phytologist
影响因子：
0
作者：
Haixia Wang;F. Trusch;Dionne Turnbull;C. Aguilera-Galvez;Susan Breen;S. Naqvi;Jonathan D. G. Jones;I. Hein;Zhendong Tian;V. Vleeshouwers;Eleanor M. Gilroy;P. Birch
通讯作者：
Haixia Wang;F. Trusch;Dionne Turnbull;C. Aguilera-Galvez;Susan Breen;S. Naqvi;Jonathan D. G. Jones;I. Hein;Zhendong Tian;V. Vleeshouwers;Eleanor M. Gilroy;P. Birch

Exploiting breakdown in nonhost effector-target interactions to boost host disease resistance.