Abstract
The COP9 signalosome (CSN) is an essential regulator of cullin‐RING‐ubiquitin (Ub) ligases (CRLs), which ubiquitinate important cellular regulators and target them for degradation by the Ub proteasome system (UPS). The CSN exhibits deneddylating activity localized on subunit CSN5, which removes the ubiquitin‐like protein Nedd8 from the cullins of CRLs. CSN‐mediated deneddylation is an important step in the process of CRL remodeling, in which new substrate recognition units are incorporated into Ub ligases to meet changed requirements for proteolysis in cells. For instance, extensive CRL remodeling occurs during adipogenic differentiation when new CRL3s are formed. Diversification of CSN complexes during evolution is most likely another adaptation to meet different cellular requirements. Best known CSN variants are formed by different CSN subunit isoforms. For instance, in plant cells, isoforms have been identified for the MPN‐domain subunits CSN5 (CSN5A and CSN5B) and CSN6 (CSN6A and CSN6B) which form four distinct CSN variants. In mammalian cells CSNCSN7A and CSNCSN7B variants are generated by CSN7 isoforms. We demonstrate that the two variants coexist in human LiSa‐2 cells and in mouse embryonic fibroblasts. During adipogenic differentiation of LiSa‐2 cells CSN7B increases in parallel with an elevation of the total CSN complex. Permanent overexpression of Flag‐CSN7B but not of Flag‐CSN7A accelerates adipogenesis in LiSa‐2 cells indicating a specific function of the CSNCSN7B variant in stimulating adipogenesis. Silencing of CSN7A as well as of CSN7B in LiSa‐2 cells and in mouse embryonic fibroblasts (MEFs) reduces adipogenic differentiation demonstrating that both CSNCSN7A and CSNCSN7B variants are involved in the process.
Highlights
The COP9 signalosome (CSN) is an essential regulator of cullin-RING-ubiquitin (Ub) ligases (CRLs), which ubiquitinate important cellular regulators and target them for degradation by the Ub proteasome system (UPS)
Increased expression of CSN7B is accompanied with an increase of the CSN complex during adipogenic differentiation [26] indicating a unique role of the CSNCSN7B variant in adipogenesis
Overexpression of CSN7B, but not that of CSN7A, accelerates adipogenesis. These effects can be explained by a specific function of CSNCSN7B variant in stimulating adipogenesis
Summary
The COP9 signalosome (CSN) is an essential regulator of cullin-RING-ubiquitin (Ub) ligases (CRLs), which ubiquitinate important cellular regulators and target them for degradation by the Ub proteasome system (UPS). Silencing of CSN7A as well as of CSN7B in LiSa-2 cells and in mouse embryonic fibroblasts (MEFs) reduces adipogenic differentiation demonstrating that both CSNCSN7A and CSNCSN7B variants are involved in the process. As shown by mass spectrometry (MS) [3,4], cryoelectron microscopy (cryo-EM) [5] and crystal structure analysis [6] each complex contains a single copy of each subunit It is composed of six ProteasomeCOP9 signalosome-Initiation factor eIF3 (PCI)domain subunits including CSN1-4, CSN7, and CSN8 and two MOV34-Pad1-N-terminal (MPN)-domain subunits called CSN5 and CSN6. Abbreviations CAND1, cullin-associated and neddylation-dissociated 1; CRL, cullin-RING-ubiquitin Ligase; CSN, COP9 signalosome; MEFs, mouse embryonic fibroblasts; MPN, MOV34-Pad1-N-terminal; ORO, Oil-Red-O; PCI, proteasome-COP9 signalosome-Initiation factor eIF3; SRS, substrate recognition subunit. CSN5A- and CSN5B-containing variants play unique roles in plant development [4,8]
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