Compositions and methods are provided for treating NF-.kappa.B-related conditions. In particular, the invention provides a stimulus-inducible IKK signalsome, and components and variants thereof. An IKK signalsome or component thereof may be used, for example, to identify antibodies and other modulating agents that inhibit or activate signal transduction via the NF-.kappa.B cascade. IKK signalsome, components thereof and/or modulating agents may also be used for the treatment of diseases associated with NF-.kappa.B activation.