Role of the COP9 Signalosome (CSN) in Cardiovascular Diseases

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.

A new activator of esterase D decreases blood cholesterol level through ESD/JAB1/ABCA1 pathway

“…In line with previous report, JAB1 potent protective activities in CVDs (Milic et al, 2019; Schwarz et al, 2017). Similarly, we discovered that the protein JAB1 could increase ABCA1 activity and promote cholesterol efflux; thus, preventing the formation oxLDL‐induced foam cells.…”

CSN8 is a key regulator in hypoxia-induced epithelial–mesenchymal transition and dormancy of colorectal cancer cells

“…HIF-1α is a short-lived protein and is ubiquitinated and degraded through the von Hippel-Lindau protein (pVHL)-E3 ubiquitin ligase pathway at normoxia [2]. CSN is reportedly associated with deubiquitination activity [6]. The ubiquitination assay showed that CSN8 overexpression could decrease HIF-1α ubiquitination (Fig.…”

“…The COP9 signalosome (CSN) is an evolutionarily conserved protein complex composed of 8 subunits (CSN1-CSN8) in higher eukaryotes, and plays an important role in ubiquitin-mediated protein degradation [6]. Previous reports indicated that the subunit of CSN, such as CSN6, is involved the malignant process of cancer [7].…”

“…Previous reports indicated that the subunit of CSN, such as CSN6, is involved the malignant process of cancer [7]. CSN8, the smallest and least conserved subunit among the eight subunits of CSN, is essential for peripheral T cell homeostasis and cardiomyocytes survival [6]. However, the role of CSN8 in cancer biology is still unclear.…”

Are Inositol Polyphosphates the Missing Link in Dynamic Cullin RING Ligase Regulation by the COP9 Signalosome?

“…The name COP9 signalosome, abbreviated as CSN, was eventually adopted to incorporate both the plant and human name, with the eight CSN subunits named CSN1 to CSN8 based on descending molecular weight. CSN mediates many fundamental and disease aspects of life, including, among others, cell cycle control, DNA repair, stemness, development, cancer and cardiovascular diseases [6,7,8,9,10].…”