A structure-function analysis of USP7 and NF-kB interaction.

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Inflammation is the complex biological response of the body's immune system to harmful stimuli, such as microbes, tissue damage or irritants. It is a protective attempt to remove the cause of injury as well as initiate the healing process for the affected tissue or organ. In the absence of inflammation, wounds and infections would never heal and progressive destruction of the affected tissue would eventually lead to serious illness or death. However, inflammation which runs unchecked can also lead to a host of diseases including inflammatory bowel disease, rheumatoid arthritis, autoimmunity, sepsis and atherosclerosis. Recent research has also revealed a role for unregulated or dysregulated inflammatory processes in cancer and neurodegeneration. The proposed research will focus on a family of proteins collectively known as Nuclear Factor kappaB (NF-kB). NF-kB is a critical regulator of gene expression and plays key roles in the immune response to infection and inflammation. The triggers of such responses may include microbes or their associated products as well as signals from neighbouring cells or tissues. These stimuli induce NF-kB to increase the expression of genes that encode for pro-inflammatory factors such as cytokines and chemokines which orchestrate the movement and activation of immune cells to sites of infection or injury. While these processes are essential for the clearance of infection and the repair of damaged tissue, they pose serious threats to healthy tissue and can cause severe damage in areas of inflammation. For this reason the expression of these pro-inflammatory mediators by NF-kB is normally tightly controlled. However in certain diseases, including those listed above, NF-kB is inadequately regulated and sustained expression of these potentially harmful mediators of inflammation occurs. As a result, NF-kB is considered an important target for the development of new therapies to prevent inflammation in the treatment of inflammatory diseases.In recent years it has emerged that the controlled destruction of NF-kB proteins is an important way used by the immune system to reduce the production of pro-inflammatory factors. Our previous studies discovered a protein called USP7 that prevents the destruction of NF-kB by interacting directly with it. We hypothesise that interfering with the interaction of these two proteins will reduce NF-kB protein levels and thereby reduce inflammation. In this proposal we aim to understand in detail how USP7 and NF-kB interact and to investigate the consequences of interfering with this interaction on the function of immune cells. The information provided from these studies could be used to develop new drugs in the future that inhibit NF-kB activity to reduce inflammation in the treatment of inflammatory disease.