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Sci. STKE, 27 March 2007
Vol. 2007, Issue 379, p. tw102
[DOI: 10.1126/stke.3792007tw102]


Ubiquitin Removing Ubiquitin to Regulate NF-{kappa}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 {kappa}B (NF-{kappa}B) induces I{kappa}B{alpha} transcription, restoring the amount of its negative regulator, I{kappa}B{alpha}, in the cell. However, the rapidity with which functional I{kappa}B{alpha} recovers implies the existence of other mechanisms to stabilize I{kappa}B{alpha}, even in the face of phosphorylation by I{kappa}B kinase beta (IKKbeta). This event leads to ubiquitinylation of I{kappa}B{alpha}, targeting it for proteasomal degradation and resulting in the release of active NF-{kappa}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, SCFbetaTrCP, ubiquitinylates I{kappa}B{alpha}. The authors performed coimmunoprecipitation studies that established that CSN2 associated with I{kappa}B{alpha} after treatment of transfected HeLa cells with tumor necrosis factor-{alpha} (TNF-{alpha}). Through coimmunoprecipitation and electrophoretic mobility shift assays, and knockdown of CSN2 by small interfering RNA (siRNA), the authors showed that the recovery in I{kappa}B{alpha} after treatment with TNF-{alpha} was much reduced in CSN2-deficient cells compared with control cells. Earlier accumulation and enhanced amounts of ubiquitinylated I{kappa}B{alpha} 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 I{kappa}B{alpha} after TNF-{alpha}-stimulated degradation compared with control cells. In vitro DUB assays, using ubiquitinylated I{kappa}B{alpha} as a substrate, demonstrated that both purified CSN and USP15 deubiquitinylated I{kappa}B{alpha}. Together, these data demonstrate a previously unknown role for CSN in regulating NF-{kappa}B activity through the stabilization of I{kappa}B{alpha}.

K. Schweitzer, P. M. Bozko, W. Dubiel, M. Naumann, CSN controls NF-{kappa}B by deubiquitinylation of I{kappa}B{alpha}. EMBO J. 26, 1532-1541 (2007). [PubMed]

Citation: J. F. Foley, Removing Ubiquitin to Regulate NF-{kappa}B Activity. Sci. STKE 2007, tw102 (2007).

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