Control of NF-kB and inflammation by COMMD proteins

描述(申请人提供)：核因子-kB是一种转录因子，调节炎症和细胞生存的关键因子的表达，因此在多种人类疾病中发挥核心作用。核因子-kB受IKB调节，IKB将转录因子隔离在细胞质中。作为对各种刺激的反应，IKB被瞬时降解，允许核转录因子-kB移位到细胞核中，在那里它激活了一系列基因的表达。有趣的是，核因子-kB激活的基因通常是特定于相关细胞类型和刺激的，我们目前对这一途径的了解不能完全解释这些不同的影响。我们最近发现了一类新的抑制核因子-kB的保守因子家族，称为COMMD蛋白。COMMD1是该家族的原型，作用于细胞核，在那里它被招募到染色质，并促进启动子结合的NF-kB的释放。我们的最新数据表明，COMMD1通过一种称为ECS-SOCS1的多聚体泛素连接酶介导核因子-kB亚基的泛素化和蛋白酶体降解。由于核因子-kB的泛素化与其从启动子位点释放有关，COMMD1介导的泛素化为其影响染色质结合的核因子-kB提供了一种机制。此外，虽然IKB具有广泛的抑制性，但单个COMMD对kB反应基因的特定亚组有影响。我们推测，COMMD蛋白通过招募泛素连接酶来局部抑制NF-kB，从而在特定的基因靶点发挥作用。因此，我们假设多成员COMMD家族在提供核因子-kB途径的特异性方面起着关键作用。我们认为，COMMD通过对核因子-kB的作用，可能参与炎症和肿瘤的发生。本项目的总体目标是：确定COMMD1介导核因子-kB泛素化(AIM1)的机制，阐明控制COMMD1活性的机制(AIM2)，并研究COMMD1蛋白在基因调控中的差异作用(AIM3)。专业描述：核因子-kB是基因表达的主要调节者，负责启动炎症中的关键基因。因此，在以炎症为共同特征的疾病中，核因子-kB发挥着核心作用。我们已经发现了一组名为COMMD蛋白的因子，它们抑制了NF-kB。这项提案的总体目标是了解COMMD蛋白是如何工作的，因为它们的作用机制可能为设计具有广泛潜在应用范围的抗炎疗法提供线索

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