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: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=760590
• 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细胞，专门用于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细胞会导致组织损伤。从T细胞的发育阶段到它们对感染产生的反应，严格调控T细胞是至关重要的。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理解T细胞基因表达在其生命的不同阶段的变化，然而，细胞命运和功能调节的全貌需要我们进一步探索具体发生在蛋白质水平上的事件。一个最重要的细胞调节机制是由一种被称为泛素化的蛋白质修饰介导的，即一个小的泛素分子或泛素链被添加到蛋白质中。这种修饰可以导致目标蛋白的破坏，也可以改变其活性或细胞定位。被称为去泛素酶的特殊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尚未被充分研究的领域，至少在T细胞生物学领域，去泛素酶家族，UCH家族。我们已经证明这个家族的一个成员BAP1在CD8 T细胞的反应中是重要的。我们将探讨BAP1介导这种作用的机制。为此，我们将揭示BAP1在T细胞中的相互作用伙伴，确定BAP1在T细胞中的作用需要哪些相互作用，并评估其对基因表达的影响。对于UCH去泛素酶家族的其他成员，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细胞生命的这些阶段中发挥作用，从胸腺到成熟的记忆T细胞。利用T细胞发育和反应作为模型，我们的研究计划将进一步加深我们对介导细胞命运和细胞规格的调节过程的理解。更有针对性的是，我们将有助于进一步了解在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方面的作用。