Chair of Vascular Biology, Institute for Stroke and Dementia Research (ISD), Klinikum der Universität München (KUM), Ludwig-Maximilians-University (LMU), 81377 Munich, Germany.
Munich Heart Alliance, 80802 Munich, Germany.
Biomolecules. 2019 Jun 5;9(6):217. doi: 10.3390/biom9060217.
The constitutive photomorphogenesis 9 (COP9) signalosome (CSN) is an evolutionarily conserved multi-protein complex, consisting of eight subunits termed CSN1-CSN8. The main biochemical function of the CSN is the control of protein degradation via the ubiquitin-proteasome-system through regulation of cullin-RING E3-ligase (CRL) activity by deNEDDylation of cullins, but the CSN also serves as a docking platform for signaling proteins. The catalytic deNEDDylase (isopeptidase) activity of the complex is executed by CSN5, but only efficiently occurs in the three-dimensional architectural context of the complex. Due to its positioning in a central cellular pathway connected to cell responses such as cell-cycle, proliferation, and signaling, the CSN has been implicated in several human diseases, with most evidence available for a role in cancer. However, emerging evidence also suggests that the CSN is involved in inflammation and cardiovascular diseases. This is both due to its role in controlling CRLs, regulating components of key inflammatory pathways such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and complex-independent interactions of subunits such as CSN5 with inflammatory proteins. In this case, we summarize and discuss studies suggesting that the CSN may have a key role in cardiovascular diseases such as atherosclerosis and heart failure. We discuss the implicated molecular mechanisms ranging from inflammatory NF-κB signaling to proteotoxicity and necrosis, covering disease-relevant cell types such as myeloid and endothelial cells or cardiomyocytes. While the CSN is considered to be disease-exacerbating in most cancer entities, the cardiovascular studies suggest potent protective activities in the vasculature and heart. The underlying mechanisms and potential therapeutic avenues will be critically discussed.
组成型光形态建成 9（COP9）信号体（CSN）是一个进化上保守的多蛋白复合物，由八个亚基组成，称为 CSN1-CSN8。CSN 的主要生化功能是通过调节 cullin-RING E3 连接酶（CRL）的活性来控制通过泛素-蛋白酶体系统进行的蛋白质降解，通过对 cullin 的去 NEDDylation 来实现，但 CSN 也作为信号蛋白的对接平台。该复合物的催化去 NEDDylase（肽基水解酶）活性由 CSN5 执行，但仅在复合物的三维结构环境中才能有效地发生。由于其定位于与细胞反应（如细胞周期、增殖和信号转导）相关的细胞内途径，CSN 已被牵连到几种人类疾病中，其中大多数证据表明其在癌症中发挥作用。然而，新出现的证据也表明 CSN 参与炎症和心血管疾病。这既是由于其在控制 CRL 中的作用，调节核因子 kappa-轻链增强子的激活 B 细胞（NF-κB）等关键炎症途径的组成部分，以及亚基（如 CSN5）与炎症蛋白的非复合物相互作用。在这种情况下，我们总结和讨论了表明 CSN 可能在动脉粥样硬化和心力衰竭等心血管疾病中发挥关键作用的研究。我们讨论了从炎症性 NF-κB 信号传导到蛋白毒性和坏死的涉及分子机制，涵盖了相关的细胞类型，如髓样细胞和内皮细胞或心肌细胞。虽然 CSN 被认为在大多数癌症实体中会加剧疾病，但心血管研究表明其在血管和心脏中具有潜在的保护作用。我们将批判性地讨论潜在的机制和潜在的治疗途径。
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