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

TLDR

Stimulation of cells with NF‑κB inducers such as LPS and IL‑1 triggers IκB‑α/β degradation and NF‑κB nuclear translocation, while the PKA catalytic subunit remains inactive when bound to IκB‑α/β in an NF‑κB–IκB–PKAc complex. The study demonstrates that NF‑κB transcriptional activity is regulated by phosphorylation of p65 by PKA, beyond cytosolic sequestration. IκB degradation activates PKAc independently of cAMP, leading to p65 phosphorylation. This pathway reveals a novel cAMP‑independent mechanism of PKA activation that regulates NF‑κB activity.

Abstract

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.