Hypo-phosphorylation leads to nuclear retention of NF-κB p65 due to impaired IκBα gene synthesis

Subcellular localization guided by IκBα is crucial for regulation of nuclear factor-κB function. Here, we show that p65 Rel homology domain phosphorylation mutants are transported into the nucleus after IκBα degradation, but as a consequence of lower IκBα levels their relocation to the cytosol is blocked. We demonstrate that phosphorylation of residues S205, S276, and S281 of p65 is not required for interaction between p65 and IκBα, but is pivotal for regulating cellular IκBα levels by positively affecting gene synthesis. Our findings indicate that reduction of phosphorylation leads to nuclear retention of p65, which might be partly responsible for altered transcriptional behavior of p65 serine mutants.