Regulation of Linear Ubiquitin Signaling in Innate Immunity

先天免疫中线性泛素信号传导的调节

• 批准号: MR/X036944/1
• 负责人: Benjamin Stieglitz
• 金额: $ 84.27万
• 依托单位: Queen Mary University of London
• 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=MR%2FX036944%2F1
• 关键词: Regulation; Linear; Ubiquitin; Signaling; Innate; Regulation; Linear; Ubiquitin; Signaling; Innate

Autoimmune diseases are a major burden to our society which affects a vast number of the UK population. There are about 3 million people diagnosed with conditions such as rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, or type I diabetes. These are long-term illnesses which persist through-out the patient's life which incur combined costs of 13 billion pound per year to our health system. A major contributing factor for the aetiology of autoimmune disease is the dysregulation of cellular immune signals, which result in an uncontrolled inflammatory response to certain stimuli. A central role in this process plays a molecule known as NFkappaB, which activates various genes required to trigger an inflammatory reaction. The function of NFkappaB is usually tightly regulated and only activated if an inflammatory response is beneficial. Since imbalanced activity of the NFkappaB pathway is a widely recognized cause for pathological inflammation, a major aim in the research area of autoimmune diseases is to understand the regulation of NFkappaB in detail. One of the main regulatory mechanisms is facilitated by an enzyme called LUBAC. This enzyme attaches a molecule chain know as linear poly-ubiquitin onto several components of the NFkappaB activation pathway. Although linear poly-ubiquitin is a potent activator for the inflammatory response, the mechanism which control the production of linear-poly ubiquitin is not well understood. This project focusses on the molecular characterisation of a recently identified molecule N4BP1 which regulates this activity. We aim to identify a detailed function of this protein and will deliver a molecular analysis how N4BP1 integrates into the process of linear poly-ubiquitin synthesis and attachment to target proteins. The findings of this research project will provide an atomic description about the regulatory role of N4BP1 which informs research and development programs aiming on the discovery of new therapeutic avenues for the intervention of autoinflammatory disease.

自身免疫性疾病是我们社会的重大负担，影响了大量英国人口。大约有300万人被诊断出患有类风湿关节炎，炎症性肠病，多发性硬化症或I型糖尿病。这些是长期疾病，持续到患者的生活中，每年为我们的卫生系统造成130亿磅的总成本。自身免疫性疾病病因的主要因素是细胞免疫信号的失调，这导致对某些刺激的炎症反应不受控制。在此过程中的核心作用扮演着一种称为NFKAPPAB的分子，该分子激活了触发炎症反应所需的各种基因。 NFKappab的功能通常受到严格的调节，并且仅在炎症反应是有益的情况下被激活。由于NFKAPPAB途径的不平衡活性是病理炎症的广泛认可的原因，因此自身免疫性疾病研究领域的主要目的是详细了解NFKAPPAB的调节。一种称为lubac的酶促进了主要的调节机制之一。该酶连接一个分子链被称为线性多泛素蛋白上的NFKappab激活途径的几个成分。尽管线性多泛素是炎症反应的有效活化剂，但控制线性泛素蛋白产生的机制尚不清楚。该项目的重点是调节该活性的最近确定的分子N4BP1的分子表征。我们旨在确定该蛋白质的详细功能，并将提供分子分析N4BP1如何整合到线性多泛素合成和附着到靶蛋白上的过程中。该研究项目的发现将提供有关N4BP1的监管作用的原子描述，该描述为研究与发展计划提供了旨在发现新的治疗途径以干预自身炎症疾病的。