A Cul5 E3 ubiquitin ligase complex that prevents allergic asthma

哮喘是一种慢性呼吸道炎症性疾病，影响2600万美国人，并导致 仅在美国每年就有大约3600人死亡(1a)。哮喘是一种异质性疾病，Th2 主型和Th17主型有不同的病因描述。而Th2细胞因子 在过敏性哮喘患者中更为常见，这些患者之间在 发现的Th2细胞因子的类型，疾病的严重程度，以及对当前可用的治疗的反应。IL-9的产生 Th9细胞是一种新的细胞因子，可产生T细胞，常见于过敏性哮喘患者 与疾病的严重性有关。然而，调节Th9分化和功能的机制仍然很大 未知。我们已经确定了一种新的抑制途径，限制了两者的分化和致病性 Th2和Th9细胞，对小鼠呼吸道重塑有保护作用。该途径受E3泛素调控 连接酶Cul5。支持这一点的是，我们最近培育出了仅在T细胞中缺失Cul5的小鼠，并且 确定cul5限制哮喘诱导后的气道重塑。具体地说，我们发现Cul5fl/flCD4-Cre 小鼠在屋尘后表现出肺部炎症、嗜酸性粒细胞增多、杯状细胞增生和纤维化。 粉尘暴露症。来自Cul5fl/flCD4-Cre小鼠的T细胞更有可能是Th2和Th9细胞。使用屏幕执行以下操作 为了揭示Cul5的结合伙伴，我们在T细胞中发现了三种与cul5相互作用的底物受体。基座 根据这些初步数据，我们假设cul5与这些底物中的一个或多个有关 泛素化底物的受体，从而限制Th2和Th9细胞的分化，并防止 哮喘。根据我们的初步数据，我们的长期目标是开发新的治疗策略， 哮喘患者Th2和Th9细胞关闭的Cul5途径。然而，为了有效地做到这一点，我们必须 首先确定1)cul5如何调节T细胞生物学，2)确定相互作用的伙伴如何帮助cul5发挥作用，以及 3)在机制水平上描述cul5复合体如何限制T细胞分化和致病性(即识别 底物)。在这项提案中，我们将确定Cul5如何限制T细胞分化和功能的关键方面， 从而揭示了允许Th9细胞发展和驱动哮喘的信号通路。此外，我们还将 确定促进cul5激活和功能的调控机制。此信息将提供 当我们开始开发针对Cul5的治疗以减少Th2分化时所需的关键信息 过敏性哮喘中的Th9细胞。

Asthma is a chronic inflammatory disease of the airways that affects 26 million Americans and results in approximately 3600 deaths per year in the US alone (1a). Asthma is a heterogeneous disease and both Th2 predominant and Th17 predominant forms have been described with different etiologies. While Th2 cytokines are more common in patients with allergic asthma, there is variability among these patients in regards to the types of Th2 cytokines found, severity of disease, and response to currently available therapies. IL-9 producing Th9 cells are a new cytokine producing T cell that are often found in patients with allergic asthma and correlate with disease severity. However, the mechanisms that regulate Th9 differentiation and function remain largly unknown. We have identified a novel inhibitory pathway that limits the differentiation and pathogenicity of both Th2 and Th9 cells and protects against airway remodeling in mice. This pathway is controlled by the E3 ubiquitin ligase Cul5. Supporting this, we recently generated mice in which Cul5 was deleted only in T cells, and determined that Cul5 limits airway remodeling after asthma induction. Specifically, we found that Cul5fl/flCD4-Cre mice showed increased lung inflammation, eosinophilia, goblet cell hyperplasia and fibrosis following house dust mite exposure. T cells from Cul5fl/flCD4-Cre mice were much more likely to Th2 and Th9 cells. Using a screen to reveal Cul5 binding partners, we identified three substrate receptors that cooperate with Cul5 in T cells. Based on these preliminary data we hypothesize that Cul5 associates with one or more of these substrate receptors to ubiquitylate substrates and thus limits the differentiation of Th2 and Th9 cells and prevents asthma. Based on our preliminary data, our long term goal is to develop novel therapeutic strategies that activate the Cul5 pathway to turn Th2 and Th9 cells off in patients with asthma. However, to do this effectively we must first determine 1) how Cul5 regulates T cell biology, 2) determine how interacting partners aid Cul5 function, and 3) delineate how, on a mechanistic level, Cul5 complexes limit T cell differentiation and pathogenicity (i.e identify substrates). In this proposal we will determine key aspects of how Cul5 restricts T cell differentiation and function, thus revealing the signaling pathways that allow Th9 cells to develop and drive asthma. Additionally, we will identify regulatory mechanisms that promote the activation and function of Cul5. This information will provide crucial information needed as we begin to develop therapies to target Cul5 to reduce the differentiation of Th2 and Th9 cells in allergic asthma.