HMA domain proteins as conserved targets of pathogens that exploit plasmodesmata

HMA 结构域蛋白作为利用胞间连丝的病原体的保守靶标

• 批准号: BB/X016056/1
• 负责人: Christine Faulkner
• 金额: $ 104万
• 依托单位: John Innes Centre
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FX016056%2F1
• 关键词: HMA; domain; proteins; conserved; targets

Microbial pathogens invade their hosts via a range of infection strategies that allow the pathogen to grow and reproduce. Infection can include physical processes that transform host cells and tissues to accommodate the invader, and molecular warfare in which proteins and small molecules are exchanged to impede and manipulate the other organism. At the molecular level, pathogens are armed with a repertoire of proteins and small molecules that can be delivered into host cells, targeting specific physiological processes to control cellular function. Microbial proteins that are delivered into host cells are referred to as effectors and while there are common themes amongst their function in targeting immune suppression and resource distribution, they have a wide variety of molecular targets, specific to a given microbe. Pathogen effectors from different kingdoms target host plasmodesmata, the cytoplasmic connections between cells. Plasmodesmata offer a pathway for some pathogens to pass between cells and spread through host tissues, as well as acting as conduits by which molecules can pass to sites where they are deployed in infection; effectors can pass from infected cells into uninfected cells and nutrients can pass freely from host sources to the site of infection. As might be expected, host cells usually try to close their plasmodesmata as a defence mechanism. However, several effectors that target plasmodesmata can prevent this response and maintain connectivity between host cells. Thus, plasmodesmata have emerged as a critical battleground between host and pathogen.There have been several observations of effectors from viral and fungal pathogens that target heavy metal associated (HMA) domain proteins located at plasmodesmata. That such diverse pathogens target the same class of proteins located at intercellular bridges suggests that HMA domain proteins offer significant gains during infection. Further, in many plant species HMA domains are integrated into immune receptor sequences where they act as decoys to bind the relevant effector and activate the immune receptor, triggering cell death and consequent resistance. Unfortunately, while immune receptor hijacking of effector-HMA domain interactions points to the significance of the association, it also impedes research into the role of the effector and the HMA target as it becomes masked by immune receptor activation.We recently showed that the Arabidopsis fungal pathogen Colletotrichum higginsianum produces an effector that targets a plasmodesmata-located HMA domain protein in the host. Arabidopsis does not produce immune receptors with integrated HMA domains, allowing us to investigate the role and mechanism of this interaction in infection. This will also allow us to ask how and why these effectors target plasmodesmata. As the C. higginsianum effector not only targets plasmodesmata but moves cell to cell and modifies plasmodesmata to allow large proteins to move between cells more frequently, it suggests that one effector function is to increase the capacity for molecular exchange between host cells.This proposal will use the Arabidopsis-Colletotrichum interaction to determine what function the effector and host target each play in infection. We will use structural biology to compare the interactions between the effector and target HMAs from diverse species and identify any conservation between the mechanisms by which this occurs. We will also exploit any conservation to determine if we can exchange the HMA domain in immune receptors from rice with the HMA domain from Arabidopsis targeted by Colletotrichum, and thus engineer an immune receptor that recognises the Colletotrichum effector and confers novel resistance.

微生物病原体通过一系列感染策略侵入宿主，这些策略使病原体得以生长和繁殖。感染可能包括转化宿主细胞和组织以适应入侵者的物理过程，并交换了蛋白质和小分子以阻碍和操纵其他生物体的分子战。在分子水平上，病原体武装着可以递送到宿主细胞中的蛋白质和小分子的曲目，靶向特定的生理过程以控制细胞功能。传递到宿主细胞中的微生物蛋白被称为效应子，尽管它们在靶向免疫抑制和资源分布方面的功能中存在共同的主题，但它们具有特定于给定微生物的各种分子靶标。来自不同王国的病原体效应子靶向宿主质体肿瘤，这是细胞之间的细胞质连接。疟原虫为某些病原体在细胞之间传播并通过宿主组织传播的途径，以及作为导管的作用，分子可以传递到将它们部署在感染中的部位。效应子可以从感染的细胞传播到未感染的细胞，营养可以从宿主来源自由传播到感染部位。可以预期的是，宿主细胞通常试图关闭其疟原虫作为防御机制。但是，一些靶向质量肿瘤的效应子可以防止这种响应并维持宿主细胞之间的连通性。因此，疟原虫已成为宿主和病原体之间的关键战场。已经有几种观察到靶向重金属相关（HMA）结构蛋白的病毒和真菌病原体的效应子。如此多样化的病原体靶向位于细胞间桥的同类蛋白质类别表明，HMA结构蛋白在感染过程中可带来显着增长。此外，在许多植物物种中，HMA结构域被整合到免疫受体序列中，它们充当诱饵，以结合相关效应子并激活免疫受体，触发细胞死亡并随之而来的耐药性。 Unfortunately, while immune receptor hijacking of effector-HMA domain interactions points to the significance of the association, it also impedes research into the role of the effector and the HMA target as it becomes masked by immune receptor activation.We recently showed that the Arabidopsis fungal pathogen Colletotrichum higginsianum produces an effector that targets a plasmodesmata-located HMA domain protein in the host.拟南芥不会产生具有集成的HMA结构域的免疫受体，从而使我们能够研究这种相互作用在感染中的作用和机制。这也将使我们能够询问这些效应子如何以及为什么针对质量质量。 As the C. higginsianum effector not only targets plasmodesmata but moves cell to cell and modifies plasmodesmata to allow large proteins to move between cells more frequently, it suggests that one effector function is to increase the capacity for molecular exchange between host cells.This proposal will use the Arabidopsis-Colletotrichum interaction to determine what function the effector and host target each play in infection.我们将使用结构生物学比较效应子与靶标HMA之间的相互作用，并确定发生这种情况的机制之间的任何保护。我们还将利用任何保护性，以确定是否可以从colletotrichum靶向的拟南芥中的HMA域中的HMA受体中交换HMA结构域，从而设计出一种免疫受体，可以识别colletotrichum效应子并赋予新的耐药性。