Defining the roles and functional interdependencies of linear ubiquitin-related deubiquitinases and LUBAC in TNFR1 signalling

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The human body is made up of billions of cells which communicate with each other. One way for cells to communicate is via messaging factors that are produced by one cell, travel through the space between cells and finally bind to the surface of another cell. The cell that receives the messaging factor will respond to the factor as appropriate. Such factors are particularly important in the communication of different types of immune cells with each other but also in the way immune cells and other cells communicate with each other. Usually these factors stimulate a response from the receiving cell which alerts the immune system. In some cases the receiving cell is killed by the communication factor. However, the dying cell itself responds by sending out powerful signals in the form of specific factors that are released from the dying cell. These highly potent communication factors are known as "damage" or "danger" signals and represent some of the most powerful means by which the immune system can be engaged.One of the most important factors in cell-to-cell communication is the tumour necrosis factor (TNF). TNF is crucial for fighting off one of the deadliest infections known to humankind which is caused by infectious agent that causes tuberculosis. However, given the extraordinary power of TNF, it is perhaps not surprising that this factor can also cause severe damage when it is deregulated. This is exemplified by the discovery that TNF is causative for several autoimmune diseases including rheumatoid arthritis, Crohn's disease, and psoriasis. Consequently, patients suffering from these diseases often benefit from treatment with drugs that inhibit TNF. These drugs are very costly and they also block the effects of TNF completely rather than only the disease-causing consequences of TNF without interfering with the desirable activities of TNF. The aim of our research programme is to better understand the biology of TNF and how stimulation of a receiving cell by TNF leads to different outcomes so that, in the future, we can target the disease-causing aspects of the biology of TNF more precisely.Depending on the receiving cell's make-up, TNF can either trigger a signal that alerts other cells, including immune cells, but keeps them intact or it can trigger cell death which can then alert the immune system in a different way by the release of the afore-mentioned danger signals. The precise outcome of TNF binding to the receiving cell is determined by factors within the receiving cell and we recently identified three factors which regulate this outcome. These factors have a common function and were previously not known to act together to define the outcome of a cell's stimulation by TNF. Our recently performed experiments led us to conclude that each one of these factors, apart from serving a common function in the regulation of the outcome of TNF stimulation, may also have "private" functions in the so called "TNF signalling". The aim of the research proposed here is to identify which of these functions are served by these factors in common and how do they fulfil their function specifically but also which functions are served by them "privately". We also want to uncover which parts of these proteins are responsible for the "common" and "private" functions, respectively, and how disrupting defined parts of these factors affects the cell's response to stimulation by TNF. We want to understand this at the molecular and mechanistic level but also in cellular systems and, ultimately, in the living organism. We envisage that a better understanding of the functional outcomes of stimulation by TNF, which is decisively controlled by the factors we propose to study here, will contribute to being able to distinguish the desired from the undesired functions of TNF molecularly and, consequently, to the development of therapeutic strategies which allow us to specifically target those TNF functions which cause disease.