Regulation of Linear Ubiquitin Signaling in Innate Immunity

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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.