The cold shock protein YB-1 (Y-box protein-1) in chronic T cell responses and systemic lupus erythematosus (SLE)

慢性 T 细胞反应和系统性红斑狼疮 (SLE) 中的冷休克蛋白 YB-1（Y-box 蛋白-1）

• 批准号: 292779965
• 负责人: Professorin Dr. Monika Christine Brunner-Weinzierl
• 金额: --
• 依托单位: Universitätskinderklinik
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/292779965?language=en
• 关键词: cold; shock; protein; YB; box

In the proposed study, the role of the cold shock protein YB-1 (Y-box protein-1) will be evaluated for modulating systemic lupus erythematosus (SLE) which is driven by chronic inflammation. Currently, there is no cure available. Alterations in T-cell homeostasis have been suggested to play a key role in the pathogenesis. In our previous work, we have identified YB-1 as a central molecule to drive proliferation and apoptosis of primary and malignant T cells. We showed that nuclear YB-1 is required to induce proliferation and survival. Its protein phosphorylation and subsequent translocation from the cytoplasm into the nucleus is dependent on the Rsk kinase. Inactivation of YB-1 using shRNA induced cell cycle arrest and, at least partially, abrogated cell survival. Data from SLE patients revealed that YB-1 is reduced upregulated in CD4 T cells upon T-cell activation, correlating with altered cytokine synthesis, enhanced apoptosis, and reduced cell proliferation rates. In addition, Cre-induced depletion of YB-1 in T cells led to high titers of anti-nuclear autoantibodies in a lupus-like mouse model.In the proposed project, the impact and molecular mechanisms that YB-1 has on T-cell differentiation and its relevance for SLE pathology will be addressed. Using ectopic expression of YB-1 mutants in combination with YB-1 shRNA to down-regulate the expression of endogenous YB-1, we will assign regions of YB-1 to distinct signaling pathways and, ultimately, elucidate their contributions in the context of T-cell differentiation in SLE, such as polyfunctionality determined by cytokine coexpression upon T cell stimulation or terminal differentiation (apoptosis). In this respect, we will distinguish between the impact of nuclear and cytoplasmic YB-1 localization applied to peripheral blood T cells harvested from SLE patients by using lentiviral transduction to analyze their molecular and functional characteristics. Using the NZB/W mouse model for experimental SLE, we will use cell type-specific depletion of YB-1 using CD4-Cre-inducible YB-1-deleter mice, in order to determine YB-1´s role in T-cell differentiation in the course of the disease. Results will give comprehensive insights into the roles of YB-1 in T-cell homeostasis and differentiation to validate the option to target it for the selective immune modulation of SLE.

在拟议的研究中，将评估冷休克蛋白YB-1（Y-box蛋白-1）在调节慢性炎症驱动的系统性红斑狼疮（SLE）中的作用。目前还没有治愈方法。T细胞稳态的改变已被认为在发病机制中起关键作用。在我们以前的工作中，我们已经确定YB-1作为一个中心分子，以驱动增殖和凋亡的原发性和恶性T细胞。我们发现，核YB-1是诱导增殖和存活所必需的。其蛋白磷酸化和随后从细胞质易位到细胞核依赖于Rsk激酶。使用shRNA灭活YB-1诱导细胞周期停滞，并且至少部分地废除细胞存活。来自SLE患者的数据显示，在T细胞活化后，YB-1在CD 4 T细胞中减少上调，与改变的细胞因子合成、增强的细胞凋亡和降低的细胞增殖速率相关。此外，在狼疮样小鼠模型中，Cre诱导的T细胞中YB-1的耗竭导致高滴度的抗核自身抗体。在拟议的项目中，YB-1对T细胞分化的影响和分子机制及其与SLE病理学的相关性将得到解决。使用异位表达的YB-1突变体与YB-1的shRNA下调内源性YB-1的表达，我们将分配区域的YB-1不同的信号通路，并最终阐明其贡献的背景下，T细胞分化在SLE，如多功能性确定的T细胞刺激或终末分化（凋亡）后的细胞因子共表达。在这方面，我们将区分核和细胞质YB-1定位应用于外周血T细胞收获SLE患者通过使用慢病毒转导的影响，分析其分子和功能特性。使用NZB/W小鼠实验性SLE模型，我们将使用CD 4-Cre诱导的YB-1-deleter小鼠对YB-1进行细胞类型特异性耗竭，以确定YB-1在疾病过程中在T细胞分化中的作用。结果将全面了解YB-1在T细胞稳态和分化中的作用，以验证靶向其用于SLE选择性免疫调节的选择。