The role of UCH family deubiquitinases in T cell biology

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T cells are white blood cells that develop in the thymus and are specialized in the protection of the body against infections or defective cells. On the other hand, a poorly controlled T cell response or a poorly developed T cell can lead to tissue damage. It is crucially important that T cells be tightly regulated, from their developmental stages to the responses they generate against infections. Our goal is to understand the molecular events that allow the generation of a productive and protective T cell response. More recent scientific efforts have been largely made towards understanding T cell gene expression changes at different stages of its life, however a full picture of regulation of cell fate and function requires that we explore further the events that occur specifically at the protein level. One of the most important cellular regulatory mechanisms is mediated by a modification of proteins termed ubiquitylation, where a small ubiquitin molecule or chain of ubiquitins is added to a protein. This modification can result in the targeted protein's destruction but also in a change in its activity or cellular localization. Specialized enzymes called deubiquitinases can remove ubiquitin molecules. There is evidence indicating that deubiquitylation is an important regulator of T cell development and response. Our research will be focused on a vastly understudied, at least in T cell biology, family of deubiquitinases, the UCH family. We have demonstrated that one member of this family, BAP1, is important in the response of CD8 T cells. We will explore the mechanisms through which BAP1 mediates this effect. To do so we will uncover BAP1's interacting partners in T cells, determine which of these interactions is required for the role BAP1 has in T cells and evaluate the impact it has on gene expression. For the other members of the UCH deubiquitinase family, there is currently no information on the role they may have in the development of T cells and in their response. We will manipulate their expression levels to assess whether these play a role at either of these stages of the T cell's life, from the thymus to the mature memory T cell. Using T cell development and responses as a model, our research program will further our understanding of the regulatory processes that mediate cell fate and cell specification. More pointedly, we will contribute to further understanding the importance of the balance between ubiquitylation and deubiquitylation in T cell biology and we will study the role of a poorly understood protein sub-family in this context.