Structure-Function Analyses of Plant NLR receptors

植物是各种微生物的营养来源。其中许多会降低植物的适应性和生产力，因此是病原体。植物病原体危害农作物，特别是在发展中地区，那里昂贵的（通常是不可持续的）杀真菌剂和杀虫剂超出了大多数农民的经济能力。植物病害造成的产量损失也是“水分损失”，因为这种资源往往在病害摧毁作物之前就已投入。因此，通过合理部署植物免疫系统来成功防治植物病害将直接有助于人类和环境健康，并节省大量水资源。植物拥有一个复杂的免疫系统，该系统锚定在一个称为NLR受体的蛋白质家族的功能中，该蛋白质家族检测病原体的存在，并在受感染的细胞内和周围触发一系列事件，阻止病原体的生长。植物NLR功能的不断定义使植物育种受益匪浅。对NLR功能的机理理解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，现在至关重要的是要了解信号感受器在感染前是如何组织的，它们被激活的精确机制，以及这种激活如何转化为适当的输出响应。因此，拟议的研究项目的最广泛的影响将显着通知翻译到作物物种和人类健康。该项目侧重于NLR蛋白超家族的细胞内受体，这是植物和动物先天免疫系统中病原体检测的关键。NLR最初于20世纪90年代中期在植物中被发现，是植物抗病性的主要基础，并且在世纪以来一直被作物育种者作为“抗病基因”进行操纵，最初并不知情。NLR随后在动物中被发现，它们在调节感染性和自身免疫性疾病的先天免疫信号传导中发挥重要作用。一旦被激活，NLR指导复杂的输出响应，最终限制病原体的生长。尽管NLR在植物和动物的先天免疫中起着核心作用，但迄今为止还没有可推广的模型描述NLR在识别微生物信号后如何从非活性静息状态转变为活性信号传导状态。填补这一空白是植物和动物先天免疫研究中与NLR生物学相关的关键未解决的研究问题，也是本项目的重点。该项目旨在理解跨越NLR模块性的广泛范围的特定机制范例，以阐明NLR激活的核心原理，具体而言：（1）作为天然存在的效应子激活的最小TIR唯一结构域（RBA 1）;和（2）作为一个称为ADR 1蛋白的“辅助”NLR的小家族，其使用典型机制来控制细胞死亡，但使用非-该奖项反映了NSF的法定使命，并通过使用基金会的知识价值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.