Control of NF-kB and inflammation by COMMD proteins

COMMD 蛋白对 NF-kB 和炎症的控制

• 批准号: 7350877
• 负责人: Ezra Burstein
• 金额: $ 20.38万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-01 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7350877
• 关键词: Accounting; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Autoimmune Diseases; Binding; Cell Nucleus; Cell Survival; Chromatin; Complex; Cytoplasm; Data; Disease; Event; Family; Family member; Feedback; Figs - dietary; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Genetic Transcription; Goals; Individual; Inflammation; Inflammatory; Knowledge; Link; Lysine; Maps; Mediating; Modeling; Molecular; NF-kappa B; Names; Pathway interactions; Play; Post-Translational Protein Processing; Proteins; Range; Recruitment Activity; Regulation; Research Personnel; Role; Site; Specificity; Stimulus; System; Time; Ubiquitination; Work; base; cell type; design; dimer; human disease; inhibitor/antagonist; member; novel; programs; promoter; protein function; prototype; response; transcription factor; tumorigenesis; ubiquitin ligase

DESCRIPTION (provided by applicant): NF-kB is a transcription factor that regulates expression of factors critical to inflammation and cell survival, and thus plays a central role in multiple human diseases. NF-kB is regulated by IkB which sequesters the transcription factor in the cytoplasm. In response to a variety of stimuli, IkB is transiently degraded allowing translocation of NF-kB into the nucleus where it activates expression of a wide array of genes. Interestingly, the genes that NF-kB activates are often specific to the cell type and stimulus in question and our current knowledge of this pathway cannot fully account for these differential effects. We recently discovered a novel family of conserved factors that inhibit NF-kB, called COMMD proteins. COMMD1, the prototype of this family, acts in the nucleus where it is recruited to chromatin and promotes the release of promoter-bound NF-kB. Our most recent data indicate that COMMD1 mediates ubiquitination and proteasomal degradation of NF-kB subunits through a multimeric ubiquitin ligase known as ECS-SOCS1. Since ubiquitination of NF-kB has been previously linked to its release from promoter sites, COMMD1-mediated ubiquitination provides a mechanism for its effects on chromatin-bound NF-kB. In addition, while IkB is broadly inhibitory, individual COMMDs have effects on specific subsets of kB-responsive genes. We speculate that COMMD proteins function at specific gene targets by recruiting a ubiquitin ligase to locally inhibit NF-kB. Therefore, we hypothesize that the multi-member COMMD family plays a critical role in providing specificity to the NF-kB pathway. We believe that through their effects on NF-kB, COMMDs are likely involved in inflammation and oncogenesis. The overall goals of this project are: to determine the mechanism by which COMMD1 mediates NF-kB ubiquitination (AIM 1), to elucidate the mechanisms that control the activity of COMMD1 (AIM 2) and to investigate the differential effects of COMMD proteins on gene regulation (AIM 3). Lay Description: NF-kB is a master regulator of gene expression that is responsible for turning on genes critical in inflammation. Hence, NF-kB plays a central role in diseases that have inflammation as a common feature. We have discovered a group of factors named COMMD proteins that inhibit NF-kB. The overall goal of this proposal is to understand how COMMD proteins work since their mechanism of action might provide clues to design anti-inflammatory therapies with a broad range of potential applications

描述（由申请人提供）：NF-kB是一种转录因子，调节炎症和细胞存活关键因子的表达，因此在多种人类疾病中发挥核心作用。NF-kB受IkB调节，IkB将转录因子隔离在细胞质中。响应于各种刺激，IkB被瞬时降解，允许NF-κ B易位到细胞核中，在那里它激活多种基因的表达。有趣的是，NF-kB激活的基因通常对所讨论的细胞类型和刺激具有特异性，我们目前对该途径的了解不能完全解释这些差异效应。我们最近发现了一个新的保守因子家族，抑制NF-κ B，称为COMMD蛋白。COMMD 1是该家族的原型，在细胞核中起作用，在那里它被招募到染色质并促进启动子结合的NF-κ B的释放。我们最近的数据表明，COMMD 1介导的泛素化和蛋白酶体降解NF-κ B亚基通过多聚体泛素连接酶称为ECS-SOCS 1。由于NF-kB的泛素化与其从启动子位点的释放有关，因此COMMD 1介导的泛素化提供了其对染色质结合的NF-kB的影响的机制。此外，虽然IkB具有广泛的抑制作用，但单个COMMD对kB反应基因的特定子集有影响。我们推测COMMD蛋白通过募集泛素连接酶来局部抑制NF-κ B，从而在特定的基因靶点发挥作用。因此，我们假设多成员COMMD家族在为NF-κ B通路提供特异性方面起着关键作用。我们认为，通过对NF-kB的影响，COMMDs可能参与炎症和肿瘤发生。本项目的总体目标是：确定COMMD 1介导NF-κ B泛素化的机制（AIM 1），阐明控制COMMD 1活性的机制（AIM 2），并研究COMMD蛋白对基因调控的差异效应（AIM 3）。NF-kB是基因表达的主要调节因子，负责打开炎症中关键基因。因此，NF-kB在以炎症为共同特征的疾病中起着核心作用。我们已经发现了一组名为COMMD蛋白的因子抑制NF-κ B。该提案的总体目标是了解COMMD蛋白如何工作，因为它们的作用机制可能为设计具有广泛潜在应用的抗炎疗法提供线索