AbstractA great variety of signalling pathways regulating inflammation, cell development and cell survival require NF‐κB transcription factors, which are normally inactive due to binding to inhibitors, such as IκBα. The canonical activation pathway of NF‐κB is initiated by phosphorylation of the inhibitor by an IκB kinase (IKK) complex triggering ubiquitination of IκB molecules by SCF‐type E3‐ligase complexes and rapid degradation by 26S‐proteasomes. The ubiquitination machinery is regulated by the COP9 signalosome (CSN). We show that IκB kinases interact with the CSN‐complex, as well as the SCF‐ubiquitination machinery, providing an explanation for the rapid signalling‐induced ubiquitination and degradation of IκBα. Furthermore, we reveal that IKK’s phosphorylate not only IκBα, but also the CSN‐subunit Csn5/JAB1 (c‐Jun activation domain binding protein‐1) and that IKK2 influences ubiquitination of Csn5/JAB1. Our observations imply that the CSN complex acts as an inhibitor of constitutive NF‐κB activity in non‐activated cells. Knock‐down of Csn5/JAB1 clearly enhanced basal NF‐κB activity and improved cell survival under stress. The inhibitory effect of Csn5/JAB1 requires a functional MPN+ metalloprotease domain, which is responsible for cleaving ubiquitin‐like Nedd8‐modifications. Upon activation of cells with tumour necrosis factor‐α, the CSN complex dissociates from IKK’s allowing full and rapid activation of the NF‐κB pathway by the concerted action of interacting protein complexes.