Functional role of the ubiquitin specific protease 8 (USP8/UBPy) in T cells

泛素特异性蛋白酶 8 (USP8/UBPy) 在 T 细胞中的功能作用

基本信息

批准号：
79091578
负责人：
Privatdozent Dr. Klaus-Peter Knobeloch
金额：
--
依托单位：
Institut für Neuropathologie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2008
资助国家：
德国
起止时间：
2007-12-31 至 2020-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/79091578?language=en
关键词：
Functional role ubiquitin specific protease

项目摘要

Protein modification by ubiquitin controls a wide variety of basic biological processes and is counteracted by the activity of deubiquitinating enzymes. UBPy (USP8) is one of more than 80 deubiquitinating enzymes encoded in the human genome. We were able to show that UBPy regulates the stability of receptor tyrosine kinases and is essential for proper endosomal sorting in vivo. Using cre-loxP mediated gene targeting we have generated mice with T-cell specific deletion of UBPy (ΔT-UBPy) in order to analyze the function of this ubiquitin isopeptidase in T-cells, where a pleiotropy of key signalling molecules are controlled by ubiquitin mediated mechanisms. ΔT-UBPy mice show premature death and develop a severe inflammatory bowel disease (IBD). CD4+ and CD8+ single positive T-cells in thymus, lymph node and spleen are strongly reduced and upon stimulation ΔT-UBPy thymocytes showed reduced proliferative capacity. Given results reveal an essential role of UBPy in T-cell function. Using this model system we will elucidate the molecular and cellular mechanisms mediated by USP8 to gain novel insights about the role of the ubiquitin proteasome system and ubiquitin modification in T-cell signalling. A particular focus will be the regulation, specificity and functional role of ubiquitin deconjugation, which is so far poorly understood. ΔT-UBPy mice as a novel model system for IBD might also help to better understand the molecular mechanisms underlying the human autoimmune disorders Crohns- disease and ulcerative colitis.

泛素的蛋白质修饰控制着多种基本生物过程，并被去泛素化酶 (USP8) 的活性所抵消，UBPy 是人类基因组中编码的 80 多种去泛素化酶之一，我们能够证明 UBPy 可以调节稳定性。受体酪氨酸激酶，对于体内正确的内体分选至关重要，使用 cre-loxP 介导的基因靶向，我们已经产生了具有 T 细胞特异性缺失的小鼠。 UBPy (ΔT-UBPy) 是为了分析这种泛素肽酶在 T 细胞中的功能，其中关键信号分子的多效性由泛素介导的机制控制，ΔT-UBPy 小鼠表现出过早死亡并发展为严重的炎症性肠病。 IBD），胸腺、淋巴结和脾脏中的 CD4+ 和 CD8+ 单阳性 T 细胞在受到刺激后显着减少。 ΔT-UBPy 胸腺细胞的增殖能力降低。鉴于结果揭示了 UBPy 在 T 细胞功能中的重要作用，我们将阐明 USP8 介导的分子和细胞机制，以获得关于泛素蛋白酶体系统作用的新见解。 T 细胞信号转导中的泛素修饰是一个特别关注的焦点是泛素解偶联的调节、特异性和功能作用，但迄今为止人们对此知之甚少。 ΔT-UBPy 小鼠作为 IBD 的新型模型系统也可能有助于更好地了解人类自身免疫性疾病克罗恩病和溃疡性结肠炎的分子机制。