Nedd8/COP9 signalosome-dependent control of IkBs and RelA

IkB 和 RelA 的 Nedd8/COP9 信号体依赖性控制

• 批准号: 72025323
• 负责人: Professor Dr. Michael Naumann
• 金额: --
• 依托单位: Institut für Experimentelle Innere Medizin
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2008
• 资助国家: 德国
• 起止时间: 2007-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/72025323?language=en
• 关键词: Nedd8; COP9; signalosome; dependent; control

Activation and control of the ubiquitous transcription factor nuclear factor kappa B (NF-κB) involves complex signal transduction processes. Our recent results have shown that the multiprotein complex COP9 signalosome (CSN) exerts certain functions in the control of the NF-κB activity in tumour necrosis factor receptor (TNFR) and T-cell receptor (TCR)-stimulated cells. The CSN possesses an intrinsic metalloprotease activity, which allows the removal of the Ubiquitin-like (Ubl) protein NEDD8 (deneddylation) from Cullin-RING ubiquitin-ligases (CRLs). Further, the CSN associates with deubiquitinylases (DUBs), which regulate the activity of CRLs and there substrate molecules. To date, the CSN-dependent processes, which control the NF-κB transcription factor RelA, and the Ubl- as well as DUB-dependent mechanisms in the control of the NF-κB system are incompletely understood. In the research proposal we plan to address the following topics in TNFR-induced cells i) analysis of the impact of the CSN, Ubiquitin and Ubls on RelA regulation, ii) identification of regulatory NF-κB factors, which are targeted by Ubls and iii) characterisation of the regulatory functions of DUBs in the NF-κB system and performance of a DUB-specific siRNA screen comprising all known human DUBs. Taken together, the proposed project could reveal novel insights into CSN-, Ubiquitin-, Ubl- and DUB-dependent regulatory functions in the NF-κB system.

普遍存在的转录因子核因子kappa B（NF-κB）的激活和控制涉及复杂的信号转导过程。我们最近的研究结果表明，在肿瘤坏死因子受体（TNFR）和T细胞受体（TCR）刺激的细胞中，多蛋白复合物COP 9信号体（CSN）在控制NF-κB活性中发挥一定的功能。CSN具有内在的金属蛋白酶活性，其允许从Cullin-RING泛素连接酶（CRL）中去除泛素样（Ubl）蛋白NEDD 8（去脱氧化）。此外，CSN与去泛素化酶（DUB）缔合，其调节CRL及其底物分子的活性。迄今为止，控制NF-κB转录因子RelA的CSN依赖性过程以及控制NF-κB系统的Ubl和DUB依赖性机制尚未完全了解。在研究提案中，我们计划在TNFR诱导的细胞中解决以下主题：i）分析CSN、泛素和Ubls对RelA调节的影响，ii）鉴定Ubls靶向的调节性NF-κB因子，iii）表征DUB在NF-κB系统中的调节功能，并进行包括所有已知人DUB的DUB特异性siRNA筛选。综上所述，所提出的项目可以揭示NF-κB系统中CSN-，泛素-，Ubl-和DUB-依赖性调节功能的新见解。