Nedd8/COP9 signalosome-dependent control of IkBs and RelA

核转录因子kappaB(NF-κB)的激活和调控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和T细胞受体刺激的细胞中，多蛋白复合体COP9信号体(Csn)在控制核因子-κB活性方面发挥了一定的作用。CSN具有固有的金属蛋白酶活性，使泛素样蛋白NEDD8(去动力)从库林环泛素连接酶(CRL)中去除。此外，CSN与去泛素酶(DUBS)结合，DUBS调节CRL及其底物分子的活性。到目前为止，控制NF-κB转录因子RelA的csn依赖的过程，以及控制NF-κB系统的Ub1和DUB依赖的机制还不完全清楚。在这项研究提案中，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调控的影响，ii)识别Ubls靶向的调节性NF-κB因子，以及iii)鉴定Dub在NF-κB系统中的调控功能，以及包含所有已知人类Dub的Dub特异性siRNA屏的性能。综上所述，拟议的项目可能揭示对依赖于csn、泛素、Ub1和DUB的NF-κB系统调控功能的新见解。

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.