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Review
. 2015 Mar 20;5(1):33-52.
eCollection 2015.

The COP9 signalosome and vascular function: intriguing possibilities?

Douglas S Martin  1 , Xuejun Wang  1
Affiliations
Review

The COP9 signalosome and vascular function: intriguing possibilities?

Douglas S Martin et al. Am J Cardiovasc Dis. .

Abstract

Disorders of vascular function contribute importantly to cardiovascular disease which represents a substantial cause of morbidity and mortality worldwide. An emerging paradigm in the study of cardiovascular diseases is that protein ubiquitination and turnover represent key pathological mechanisms. Our understanding of these processes in the vasculature is growing but remains incomplete. Since protein ubiquitination and turnover can represent a terminal event in the life of a given protein, entry into these pathways must be highly regulated. However, at present understanding of these regulatory mechanisms, particularly in the vasculature, is fragmentary. The COP9 (constitutive photomorphogenic mutant 9) signalosome (CSN) is a heteromeric protein complex implicated in the control of protein degradation. The CSN participates critically in the control of Cullin Ring Ligases (CRLs), at least in part via the detachment of a small protein, Nedd8 (deneddylation). CRLs are one of the largest groups of ubiquitin ligases, which represent the most selective control point for protein ubiquitination. Thus, the CSN by virtue of its ability to control the CRLs ubiquitin ligase activity is ideally positioned to effect selective modulation of protein turnover. This review surveys currently available data regarding the potential role of the CSN in control of vascular function. Data potentially linking the CSN to control of regulatory proteins involved in vascular smooth muscle proliferation and to vascular smooth muscle contraction are presented with the intent of providing potentially intriguing possibilities for future investigation.

Keywords: The COP9 signalosome; cullin-RING ligases; ubiquitination; vascular smooth muscle contraction; vascular smooth muscle proliferation.

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Figures

Figure 1
Figure 1
A summary of potential CSN targets in vasculature. The CSN is a heteromeric complex consisting of 8 subunits, CSN1~CSN8. The CSN is responsible for cullin deneddylation, with the deneddylase activity residing in CSN5. Neddylation/deneddylation is a key mechanism for controlling the activity of cullin RING ligases (CRLs). Attachment of NEDD8 (neddylation) renders the CRL able to ubiquitinate substrates to direct them to the proteasome for degradation. One of the major actions of the CSN is to remove NEDD8 (deneddylate) and inactivate CRLs. The deneddylated form of CRLs prevents the ubiquitination and proteasomal degradation of targeted substrates. The substrate recognition receptor of the CRL allows selective targeting of substrates. Thus by controlling CRLs the CSN may provide selective control of protein turnover in vascular smooth muscle (VSM). Key target substrates that may be under CSN control and participate in VSM proliferation include the cyclin dependent kinase inhibitors, p27 and p21. The CSN may also be involved in the control of vascular contraction by modulating the ubiquitination of substrates such as the voltage gated calcium channel (VGCC), potassium channel, IP3 receptor, RhoA, soluble guanylate cyclase (sGC), super oxide dismutase (SOD1), peroxiredoxin, or IkB. In the endothelium the CSN may control ubiquitination of endothelial nitric oxide synthase (eNOS), calcineurin, cyclooxygenase or GTP cyclohydrolase 1 (GTPCH1) to modulate the production and release of endothelium dependent vasodilators or constrictors.
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