CSN controls NF-κB by deubiquitinylation of IκBα

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Abstract
The COP9 signalosome (CSN) is a conserved protein complex that regulates assembly and activity of cullin‐RING ubiquitin ligases (CRLs). Ubiquitin‐dependent degradation of the NF‐κB inhibitor IκBα preceeds nuclear translocation of NF‐κB. For the first time, we show here an inducible interaction of the CSN with IκBα and that the CSN controls IκBα and NF‐κB activity. Strikingly, disruption of the CSN by a small interfering RNA‐mediated knockdown of single CSN subunits results in a reduced re‐accumulation of IκBα and prolonged nuclear translocation of NF‐κB in TNFα‐stimulated cells. The control of IκBα by the CSN is regulated by deubiquitinylation of IκBα conferred by the CSN‐associated deubiquitinylase USP15. Protein expression levels of cullin1 and the CRL substrate adapter β‐TrCP are reduced in nonstimulated cells with a disrupted function of the CSN, which might account for an impaired basal turnover of IκBα. We propose that the CSN controls both CRL activity and stability of the CRL substrate IκBα. In consequence, basal and signal‐induced CRL‐dependent turnover of IκBα is precisely adapted to specific cellular needs.