Ubiquitin
Removing Ubiquitin to Regulate NF-
B Activity
John F. Foley
Science’s STKE, AAAS, Washington, DC 20005, USA
As part of a negative feedback mechanism, the transcription factor nuclear factor 
B (NF-B) induces IB
transcription, restoring the amount of its negative regulator, IB, in the cell. However, the rapidity with which functional IB recovers implies the existence of other mechanisms to stabilize IB, even in the face of phosphorylation by IB kinase 
(IKK). This event leads to ubiquitinylation of IB, targeting it for proteasomal degradation and resulting in the release of active NF-B. Schweitzer et al. have uncovered the crucial role that the COP9 signalosome (CSN) plays in this process. CSN is an eight-subunit (CSN1-8) protein complex that controls the activities of multisubunit cullin-RING ubiquitin ligases (CRLs), one member of which, SCFTrCP, ubiquitinylates IB. The authors performed coimmunoprecipitation studies that established that CSN2 associated with IB after treatment of transfected HeLa cells with tumor necrosis factor- (TNF-). Through coimmunoprecipitation and electrophoretic mobility shift assays, and knockdown of CSN2 by small interfering RNA (siRNA), the authors showed that the recovery in IB after treatment with TNF- was much reduced in CSN2-deficient cells compared with control cells. Earlier accumulation and enhanced amounts of ubiquitinylated IB were also seen in cells deficient in CSN2. One component of the CSN complex is USP15, a deubiquitinylase (DUB). HeLa cells transfected with a USP15-specific siRNA showed reduced recovery of IB after TNF--stimulated degradation compared with control cells. In vitro DUB assays, using ubiquitinylated IB as a substrate, demonstrated that both purified CSN and USP15 deubiquitinylated IB. Together, these data demonstrate a previously unknown role for CSN in regulating NF-B activity through the stabilization of IB.
K. Schweitzer, P. M. Bozko, W. Dubiel, M. Naumann, CSN controls NF-B by deubiquitinylation of IB. EMBO J. 26, 1532-1541 (2007). [PubMed]
