Control of IκB-α Proteolysis by Site-Specific, Signal-Induced Phosphorylation

TLDR

IκB‑α sequesters NF‑κB in the cytoplasm, and stress‑ or pathogen‑associated stimuli trigger its phosphorylation and proteolysis, releasing NF‑κB to enter the nucleus and drive transcription of defense genes. Mutating serine‑32 or serine‑36 abolishes signal‑induced phosphorylation and degradation of IκB‑α, preventing NF‑κB activation and demonstrating that phosphorylation at these sites is essential for NF‑κB signaling.

Abstract

I kappa B-alpha inhibits transcription factor NF-kappa B by retaining it in the cytoplasm. Various stimuli, typically those associated with stress or pathogens, rapidly inactivate I kappa B-alpha. This liberates NF-kappa B to translocate to the nucleus and initiate transcription of genes important for the defense of the organism. Activation of NF-kappa B correlates with phosphorylation of I kappa B-alpha and requires the proteolysis of this inhibitor. When either serine-32 or serine-36 of I kappa B-alpha was mutated, the protein did not undergo signal-induced phosphorylation or degradation, and NF-kappa B could not be activated. These results suggest that phosphorylation at one or both of these residues is critical for activation of NF-kappa B.