Regulation of Linear Ubiquitin Signaling in Innate Immunity

自身免疫性疾病是我们社会的一个主要负担，影响了英国大量人口。大约有300万人被诊断患有类风湿性关节炎、炎症性肠病、多发性硬化症或I型糖尿病。这些都是长期的疾病，持续到病人的一生，每年给我们的卫生系统带来130亿磅的综合费用。自身免疫性疾病的病因学的主要促成因素是细胞免疫信号的失调，其导致对某些刺激的不受控制的炎症反应。在这个过程中，一种名为NF κ B的分子起着核心作用，它激活了引发炎症反应所需的各种基因。NF κ B的功能通常受到严格调节，只有在炎症反应有益时才被激活。由于NF κ B通路的不平衡活性是病理性炎症的广泛公认的原因，因此自身免疫性疾病研究领域的主要目标是详细了解NF κ B的调节。其中一个主要的调节机制是由一种叫做LUBAC的酶促进的。这种酶将称为线性聚泛素的分子链连接到NF κ B活化途径的几个组分上。虽然线性多聚泛素是炎症反应的有效激活剂，但控制线性多聚泛素产生的机制还不清楚。该项目的重点是最近确定的分子N4BP1的分子特性，它调节这种活动。我们的目标是确定这种蛋白质的详细功能，并将提供N4BP1如何整合到线性多聚泛素合成和附着到靶蛋白的过程中的分子分析。该研究项目的发现将提供有关N4BP1调节作用的原子描述，为旨在发现干预自身炎症性疾病的新治疗途径的研究和开发计划提供信息。

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.