Inhibition of NF-κB activity by Iκ-Bβ in association with κB-Ras

IkappaBbeta, one of the major 1kappaB proteins, is only partially degraded in response to most extracellular signals. However, the molecular mechanism of this event is unknown. We show here that 1kappaBbeta exists in at least two different forms: one that is bound to the NF-kappaB dimer and the other bound to both NF-kappaB and KB-Ras, a Ras-like small G protein. Removal of cellular KB-Ras enhances whereas excess KB-Ras blocks induced IkappaBbeta degradation. Remarkably, KB-Ras functions in both GDP-and GTP-bound states, and mutations of the conserved guanine-binding residues Of KB-Ras abrogate its ability to block degradation of IkappaBbeta. kappaB-Ras also directly blocks the in vitro phosphorylation of IkappaBbeta by IkappaBbeta. These observations suggest that IkappaBbeta in the ternary complex is resistant to degradation by most signals. We suggest that specific signals, in addition to those that activate only IKK are essential for the complete degradation of IkappaBbeta.