The COP9 Signalosome: A Multi-DUB Complex.

Wolfgang Dubiel,Supattra Chaithongyot,Dawadschargal Dubiel,Michael Naumann

doi:10.3390/biom10071082

Wolfgang Dubiel, Supattra Chaithongyot + Show 2 more

Open Access

https://doi.org/10.3390/biom10071082

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Abstract

The COP9 signalosome (CSN) is a signaling platform controlling the cellular ubiquitylation status. It determines the activity and remodeling of ~700 cullin-RING ubiquitin ligases (CRLs), which control more than 20% of all ubiquitylation events in cells and thereby influence virtually any cellular pathway. In addition, it is associated with deubiquitylating enzymes (DUBs) protecting CRLs from autoubiquitylation and rescuing ubiquitylated proteins from degradation. The coordination of ubiquitylation and deubiquitylation by the CSN is presumably important for fine-tuning the precise formation of defined ubiquitin chains. Considering its intrinsic DUB activity specific for deneddylation of CRLs and belonging to the JAMM family as well as its associated DUBs, the CSN represents a multi-DUB complex. Two CSN-associated DUBs, the ubiquitin-specific protease 15 (USP15) and USP48 are regulators in the NF-κB signaling pathway. USP15 protects CRL1β-TrCP responsible for IκBα ubiquitylation, whereas USP48 stabilizes the nuclear pool of the NF-κB transcription factor RelA upon TNF stimulation by counteracting CRL2SOCS1. Moreover, the CSN controls the neddylation status of cells by its intrinsic DUB activity and by destabilizing the associated deneddylation enzyme 1 (DEN1). Thus, the CSN is a master regulator at the intersection between ubiquitylation and neddylation.

Highlights

The COP9 signalosome (CSN) is a multiprotein complex representing a hallmark of eukaryotic cells
Analyses of the CSN isolated from different cells by chromatography [14], pulldowns [29], immunoprecipitation [58] as well as density gradient centrifugation [17] revealed its association with additional Deubiquitylating Enzymes (DUBs), such as ubiquitin-specific protease 15 (USP15) and USP48 and presumably other DUBs as well as with deneddylation enzyme 1 (DEN1)/NEDP1/SENP8, a member of the SENP family (Figure 1)
In the review we focus on CSN associated USP15 and USP48 and their functions in the NF-κB pathway as well as on DEN1, an associated deneddylase

Summary

Introduction

The COP9 signalosome (CSN) is a multiprotein complex representing a hallmark of eukaryotic cells. CSN-mediated deneddylation is a prerequisite for the exchange of hundreds of substrate receptors (SRs) including F-box and BTB-domain SRs [45,46,47] as part of a rapid adaptation to altered protein degradation requirements [48]. In this process the CSN cooperates with Cullin-Associated and Neddylation-Dissociated 1 (CAND1) to accelerate the exchange of SRs to optimize the CRL network in response to fluctuations in substrate availability [45,46,49,50,51,52,53,54]. The CSN is a DUB of the JAMM family, controlling the Ub-dependent protein degradation mediated by CRLs, which is essential for maintaining processes such as cell cycle [56], DNA repair [57] and differentiation [48]

The CSN and Its Paralog 26S Proteasome Lid Cooperate with Diverse DUBs

CSN-DUB Interactions and Their Role in NF-κB Regulation

CSN-DEN1

Findings

Concluding Remarks