The transcriptional activity of NF-kappa B is regulated by the I kappa B-associated PKAc subunit through a cyclic AMP-independent mechanism

Stimulation of cells with inducers of NF-kappa B such as LPS and IL-1 leads to the degradation of I kappa B-alpha and I kappa B-beta proteins and translocation of NF-kappa B to the nucleus. We now demonstrate that, besides the physical partitioning of inactive NF-kappa B to the cytosol, the transcriptional activity of NF-kappa B is regulated through phosphorylation of NF-kappa B p65 by protein kinase A (PKA). The catalytic subunit of PKA (PKAc) is maintained in an inactive state through association with I kappa B-alpha or I kappa B-beta in an NF-kappa B-I kappa B-PKAc complex. Signals that cause the degradation of I kappa B result in activation of PKAc in a cAMP-independent manner and the subsequent phosphorylation of p65. Therefore, this pathway represents a novel mechanism for the cAMP-independent activation of PKA and the regulation of NF-kappa B activity.