The role of UCH family deubiquitinases in T cell biology

UCH 家族去泛素酶在 T 细胞生物学中的作用

• 批准号: RGPIN-2020-05593
• 负责人: Labrecque, Nathalie
• 金额: $ 3.06万
• 依托单位: Université de Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=717712
• 关键词: role; UCH; family; deubiquitinases; cell

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.

T细胞是在胸腺中发育的白色血细胞，专门保护身体免受感染或缺陷细胞的侵害。另一方面，控制不良的T细胞反应或发育不良的T细胞可导致组织损伤。至关重要的是，T细胞从发育阶段到它们对感染产生的反应都受到严格的调控。我们的目标是了解允许产生生产性和保护性T细胞反应的分子事件。 最近的科学努力主要是为了了解T细胞在其生命的不同阶段的基因表达变化，然而，细胞命运和功能调控的全貌需要我们进一步探索在蛋白质水平上特异性发生的事件。最重要的细胞调节机制之一是由称为泛素化的蛋白质修饰介导的，其中小泛素分子或泛素链被添加到蛋白质中。这种修饰可以导致靶蛋白的破坏，但也可以导致其活性或细胞定位的变化。称为去泛素化酶的专门酶可以去除泛素分子。有证据表明去泛素化是T细胞发育和应答的重要调节因子。 我们的研究将集中在一个广泛研究不足，至少在T细胞生物学，家庭的去泛素化酶，UCH家庭。我们已经证明，这个家族的一个成员，BAP 1，在CD8 T细胞的反应中是重要的。我们将探讨BAP 1介导这种效应的机制。为此，我们将揭示BAP 1在T细胞中的相互作用伙伴，确定BAP 1在T细胞中的作用所需的相互作用，并评估其对基因表达的影响。对于UCH去泛素化酶家族的其他成员，目前还没有关于它们在T细胞发育及其反应中可能发挥的作用的信息。我们将操纵它们的表达水平，以评估它们是否在T细胞生命的任何一个阶段发挥作用，从胸腺到成熟的记忆T细胞。 使用T细胞发育和反应作为模型，我们的研究计划将进一步我们的调节过程，介导细胞命运和细胞规格的理解。更有针对性地，我们将有助于进一步理解T细胞生物学中泛素化和去泛素化之间平衡的重要性，我们将研究一个知之甚少的蛋白质亚家族在这种情况下的作用。