Regulatory crosstalk between human Caspases & Guanylate Binding Proteins in antimicrobial host-defence

人类半胱天冬酶之间的调控串扰

• 批准号: MR/V030930/1
• 负责人: Avinash Shenoy
• 金额: $ 89.15万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FV030930%2F1
• 关键词: Regulatory; crosstalk; between; human; Caspases

Background: A prompt and proportionate response to an infectious agent is important for clearing infection. The immune system relies on early mechanisms of innate defence which appropriately guide late mechanisms deployed after a few days of infection. Both systems work in tandem and incorrect early responses can result in increased microbial spread in organs, inflammation, and tissue damage. A key role of the early response is to quickly identify the type of infection, for example whether bacterial, viral, or parasitic, and respond in a manner that is effective against the specific type of pathogen. Two families of enzymes play important roles during early immune defence, the Guanylate Binding Proteins (GBPs) and Caspases. GBPs are enzymes that convert the molecule GTP into GDP, and act as molecular on-off switches. Caspases are enzymes that act as molecular scissors and cut a range of important proteins that are involved in immunity. Molecular cutting by caspases is important for the normal functions of many proteins in cells. Together, GBPs and caspases act against diverse infectious agents and protect us. We previously showed that the family member GBP1 assists in early immune responses against the diarrhoeagenic bacterial pathogen Salmonella as well as the parasitic pathogen Toxoplasma gondii which causes types of brain disease. Others have showed that GBPs and caspases together assist in defending against diseases such as forms of bacterial diarrhoeas, tularemia, Legionnaire's disease, HIV, among others. This reflects the broad protective roles of these proteins and their importance in human infection. Interestingly, these pathogens invade and reside within our own cells, such as immune cells, brain cells, intestinal cells, where they grow and multiply. GBPs and caspases remove infected cells and prevent the growth and spread of pathogens. These enzymes are therefore crucial in human immune responses and their actions need to be better understood. How exactly GBPs and caspases cooperate remains poorly defined.Aims & approaches: Our overall goal is to understand the molecular and cellular mechanisms of how GBPs and caspases defend us against infection. Their combined actions detect infections by different microbes and set in motion a series of events that result in the loss of the infected host cell, which reduces pathogen multiplication and limits infection. We want to understand how GBPs and caspases cooperate with each other and other molecules and whether collateral damage through loss of host cells can be avoided. We newly discovered that there is a molecular interplay between caspases and GBPs that naturally suppresses inflammation during Salmonella infection. In the proposed work we will broaden this finding to other GBP enzymes and other inflammatory settings. GBPs are anchored by lipids into membranes inside cells to execute their function. Our team includes chemists who have designed new sensitive chemical probes that will help answer important questions such as when/where/how lipids anchors GBPs and control their actions. We will deploy our advanced artificial intelligence-based workflow for microscopic imaging of pathogens for fast analyses of a large amount of data and increased efficiency. We are a team of scientists with many years of experience in immunology, pathogenesis, inflammation, and chemical biology. Our proposal therefore has a high chance of being successful.Potential benefits: GBPs and caspases protect against major groups of human pathogens. Their beneficial actions could be harnessed to improve our natural defence against infections. Understand what deregulates them will enable us to prevent detrimental inflammation. Our new discoveries on their regulation will have the potential to be exploited in therapies aimed at reducing unwanted inflammation and for a better response against drug-resistant pathogens.

背景：对感染源的迅速和适当的反应对于清除感染很重要。免疫系统依赖于早期的先天防御机制，这种机制适当地指导感染几天后部署的晚期机制。这两个系统协同工作，不正确的早期反应可能会导致微生物在器官中传播增加，炎症和组织损伤。早期反应的一个关键作用是快速识别感染的类型，例如细菌、病毒或寄生虫，并以对特定类型的病原体有效的方式做出反应。两个酶家族在早期免疫防御中发挥重要作用，鸟苷结合蛋白(GBP)和半胱氨酸天冬氨酸氨基转移酶(Caspase)。Gbps是一种酶，可以将分子GTP转化为GDP，并充当分子开关。Caspase是一种酶，它充当分子剪刀，切割一系列与免疫有关的重要蛋白质。半胱氨酸天冬氨酸酶的分子切割对于细胞中许多蛋白质的正常功能非常重要。GBP和半胱氨酸天冬氨酸氨基转移酶共同作用于多种感染性病原体，保护我们。我们此前曾证明，GBP1家族成员有助于针对引起腹泻的细菌病原体沙门氏菌和导致各种脑部疾病的寄生虫弓形虫的早期免疫反应。其他研究表明，GBP和半胱氨酸天冬氨酸氨基转移酶一起有助于预防各种疾病，如细菌性腹泻、图拉热症、退伍军人症、艾滋病毒等。这反映了这些蛋白质的广泛保护作用及其在人类感染中的重要性。有趣的是，这些病原体入侵并居住在我们自己的细胞内，如免疫细胞、脑细胞、肠道细胞，它们在那里生长和繁殖。GBP和半胱氨酸天冬氨酸氨基转移酶去除受感染的细胞，防止病原体的生长和传播。因此，这些酶在人类免疫反应中至关重要，需要更好地了解它们的作用。目的与方法：我们的总体目标是了解Gbps和caspase如何防御感染的分子和细胞机制。它们的联合作用可以检测到不同微生物的感染，并启动一系列事件，导致受感染的宿主细胞丧失，从而减少病原体的繁殖并限制感染。我们想要了解GBP和caspase是如何相互以及其他分子相互作用的，以及是否可以避免因失去宿主细胞而造成的附带损害。我们新发现，在沙门氏菌感染过程中，caspase和Gbps之间存在着天然的抑制炎症的分子相互作用。在拟议的工作中，我们将把这一发现扩大到其他GBP酶和其他炎症环境。GBP被脂类固定在细胞内的膜上，以执行它们的功能。我们的团队包括设计了新的敏感化学探针的化学家，这些探针将帮助回答重要的问题，如何时/何地/如何脂类锚定GBP并控制它们的行为。我们将部署我们先进的基于人工智能的工作流程，对病原体进行显微成像，以快速分析大量数据，提高效率。我们是一支在免疫学、发病机制、炎症和化学生物学方面拥有多年经验的科学家团队。因此，我们的建议有很高的成功机会。潜在的好处：GBP和半胱氨酸天冬氨酸氨基转移酶可以抵御主要的人类病原体群。它们的有益行动可以被用来提高我们对感染的天然防御能力。了解是什么解除了对它们的管制，将使我们能够预防有害的炎症。我们在其调控方面的新发现将有潜力被用于旨在减少不必要的炎症和更好地应对耐药病原体的疗法。

项目成果

PIM1 controls GBP1 activity to limit self-damage and to guard against pathogen infection.

• DOI: 10.1126/science.adg2253
• 发表时间: 2023-10-06
• 期刊: Science (New York, N.Y.)
• 作者: Fisch D;Pfleiderer MM;Anastasakou E;Mackie GM;Wendt F;Liu X;Clough B;Lara-Reyna S;Encheva V;Snijders AP;Bando H;Yamamoto M;Beggs AD;Mercer J;Shenoy AR;Wollscheid B;Maslowski KM;Galej WP;Frickel EM
• 通讯作者: Frickel EM