No one can whistle a symphony alone - how different ubiquitin linkages cooperate to orchestrate NF-κB activity.

Although it has been known for a long time that ubiquitylation has a major role in the activation and regulation of the nuclear factor kappa B (NF-κB) pathway, recent studies have revealed that the picture is a lot more complex than originally thought. NF-κB and ubiquitylation initially became linked when it was recognised that lysine (K)48-linked ubiquitin chains are involved in the processing of NF-κB precursors and the degradation of inhibitor of kappa B (IκB) proteins. Soon thereafter, it was reported that K63-linked chains were involved in the assembly of IκB kinase (IKK)-activating complexes and required for activation of the NF-κB signalling pathway. Recently, the discovery that atypical ubiquitin linkages, including linear and K11 linkages, are also involved in the activation of NF-κB has led to the need to re-evaluate existing models of how activation of this transcription factor is initiated and regulated. It is now becoming apparent that not only the canonical types of ubiquitin chains but possibly all linkage types have to be investigated in order to fully comprehend NF-κB activation. This can be considered a turning point in our view of the regulation of one of the most important pathways of gene induction. Hence, in this Commentary, we summarise the information that is currently available and incorporate it into a new model of NF-κB activation, thereby highlighting the emerging new challenges in understanding the role of ubiquitylation in NF-κB activation.