Abstract
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.
Highlights
The constitutive photomorphogenesis 9 (COP9) signalosome (CSN) is an evolutionarily conserved multi-protein complex, consisting of eight subunits termed CSN1-CSN8
We initially studied the relationship between the COP9 signalosome (CSN) and nuclear factor (NF)-κB signaling in human umbilical vein endothelial cells (HUVECs)
We found that BM-derived macrophages (BMDMs) from Csn5∆myeloid /Apoe−/− mice exhibited reduced hypoxia-inducible factor (HIF)-1α transcriptional activity [91] and a significant reduction was observed for the HIF-1α target genes Edn1 and Opn1 upon Csn5-deletion in LPS-stimulated macrophages
Summary
The constitutive photomorphogenesis 9 (COP9) signalosome (CSN)is an evolutionarily conserved multi-protein complex with a molecular size of ~400 kDa that is found in all species and kingdoms of life, including plants, fungi, Caenorhabditis elegans, Drosophila melanogaster, and mammals [1,2,3,4,5]. The. CSN complex, inhibits the E3 ligase activity of CRLs by removing NEDD8 from the cullin adaptor core [3,27,28,29]. By recruiting specific substrate receptor F-box proteins, CSN-controlled CRL-type E3 ligases such as the SCF-type CRLs (CRL1) catalyze the ubiquitylation and proteasomal degradation (jointly referred to as the ubiquitin-proteasome system, UPS) of numerous proteins with key functions in cell cycle regulation, cell proliferation, DNA damage, and inflammatory signaling pathways [26,38,39,40,41,42]. Due to its critical control function of the UPS pathway, its role as a docking platform for cell-regulatory enzymes and, due to the various individual functions of some of its subunits, it is clear that the CSN is an integral molecular machinery guaranteeing cell homeostasis, cell survival, and normal physiological cell function at several levels. The emerging role of the CSN (PDB ID: 4D10) in these diseases is indicated
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