Structure-Function Analyses of Plant NLR receptors

植物是各种微生物的肥沃营养来源。其中许多会降低植物的适合度和生产力，因此是病原体。植物病原体破坏农作物，特别是在发展中国家，昂贵的杀菌剂和杀虫剂(通常是不可持续的)超出了大多数农民的经济承受能力。植物病害造成的产量损失也是“水分损失”，因为这种资源通常在疾病摧毁作物之前进行投资。因此，通过植物免疫系统的合理配置，成功地防治植物病害，将直接为人类和环境健康做出贡献，并节省大量的水资源。植物拥有一种复杂的免疫系统，它依赖于一种名为NLR受体的蛋白质家族的功能，该家族可以检测病原体的存在，并在受感染的细胞内和周围引发一系列事件，阻止病原体的生长。植物育种得益于目前对植物NLR功能的定义。从机理上理解NLR的功能是在作物中合理部署植物免疫系统和开发各种人类疾病治疗方法的先决条件。在植物或动物中研究NLR实验系统的研究人员认识到，现在至关重要的是了解信号合格受体在感染前是如何组织的，它们被激活的确切机制，以及这种激活如何转化为适当的输出反应。因此，拟议的研究项目的最广泛的影响将显著地为作物物种和人类健康的翻译提供信息。该项目重点关注NLR蛋白超家族的细胞内受体，这些受体在植物和动物的先天性免疫系统中对病原体检测至关重要。NLRs最初是在20世纪90年代中期在植物中发现的，是植物抗病的主要基础，最初在不知不觉中被作物育种者作为“抗病基因”操纵了一个多世纪。NLRs随后在动物中被发现，它们在调节传染病和自身免疫性疾病的先天性免疫信号方面发挥着重要作用。一旦被激活，NLR就会引导一种复杂的输出反应，最终限制病原体的生长。尽管NLRs在植物和动物的先天免疫中起着核心作用，但迄今为止还没有一个通用的模型来描述NLRs在识别微生物信号后如何从静止状态转变为活动信号状态。填补这一空白是NLR生物学在植物和动物先天免疫研究中尚未解决的关键研究问题，也是本项目的重点。这个项目旨在了解特定的机制样本，这些样本跨越了NLR模块化的广泛范围，以阐明NLR激活的核心原理，特别是：(1)作为一个自然产生的效应器激活的最小TIR结构域(RBA1)；以及(2)作为一个称为ADR1蛋白的“辅助”NLR小家族，它使用规范机制来控制细胞死亡，但非规范机制来增强传感器NLR的功能并有助于控制水杨酸水平。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Plants are fertile sources of nutrients for a variety of microbes. Many of these reduce plant fitness and productivity, and hence are pathogens. Plant pathogens devastate crops, particularly in developing areas where expensive (and often unsustainable) fungicides and pesticides are beyond the economic reach of most farmers. Yield losses due to plant disease are also "water losses", since that resource is often invested before disease decimates a crop. Hence, successfully combating plant diseases through rational deployment of the plant immune system will contribute directly to human and environmental health, and save lots of water. Plants possess a sophisticated immune system anchored in the functions of a family of protein, called NLR receptors, that detect the presence of pathogens and trigger a cascade of events in and around the infected cell that stops pathogen growth. Plant breeding has benefited from the ongoing definition of plant NLR function. A mechanistic understanding of NLR function is a prerequisite for rational deployment of the plant immune system in crops and for the development of treatments for various human diseases. Researchers investigating NLR experimental systems in either plants or animals recognize that it is now vital to understand how signal competent receptors are organized before infection, the precise mechanisms by which they are activated, and how this activation is translated in an appropriate output response. Hence, the broadest impacts of the proposed research project will significantly inform translation to crop species and to human health.This project focuses on the intracellular receptors of the NLR protein superfamily which are critical for pathogen detection in the innate immune systems of both plants and animals. Originally discovered in plants in the mid-1990s, NLRs are a major basis for disease resistance in plants and have been manipulated, unknowingly at first, by crop breeders as "disease resistance genes" for over a century. NLRs were subsequently discovered in animals, where they play a major role in regulating innate immune signaling in infectious and autoimmune disease. Once activated, NLRs direct a complex output response that ultimately restricts pathogen growth. Despite the central role of NLRs in innate immunity in plants and animals, there is to date no generalizable model describing how NLRs transition from an inactive resting state to an active signaling state after recognition of microbial signals. Filling this gap is the critical unresolved research issue pertaining to NLR biology in both plant and animal innate immune research, and is the focus of this project. This project is aimed at understanding particular mechanistic exemplars that span the wide gamut of NLR modularity in order to illuminate the core principles underlying NLR activation, specifically: (1) as a naturally occurring effector-activated minimal TIR only domain (RBA1); and (2) as a small family of "helper" NLRs called ADR1 proteins that use a canonical mechanism to control cell death but a non-canonical mechanism to enhance sensor NLR function and contribute to the control of salicylic acid levels.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.