The Transcriptional Activity of NF-κB Is Regulated by the IκB-Associated PKAc Subunit through a Cyclic AMP–Independent Mechanism

Stimulation of cells with inducers of NF-κB such as LPS and IL-1 leads to the degradation of IκB-α and IκB-β proteins and translocation of NF-κB to the nucleus. We now demonstrate that, besides the physical partitioning of inactive NF-κB to the cytosol, the transcriptional activity of NF-κB is regulated through phosphorylation of NF-κB p65 by protein kinase A (PKA). The catalytic subunit of PKA (PKAc) is maintained in an inactive state through association with IκB-α or IκB-β in an NF-κB–IκB–PKAc complex. Signals that cause the degradation of IκB 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-κB activity.