Signal-induced site-specific phosphorylation targets I kappa B alpha to the ubiquitin-proteasome pathway.

TLDR

NF‑κB is retained in the cytoplasm by IκBα, and extracellular signals trigger its phosphorylation and degradation, yet the link between phosphorylation and degradation remains unclear. Phosphorylation of serine 32 and 36 on IκBα targets the protein for ubiquitination, which keeps it associated with NF‑κB and directs its removal by the 26S proteasome, thereby linking phosphorylation to degradation.

Abstract

The transcription factor NF-kappa B is sequestered in the cytoplasm by the inhibitor protein I kappa B alpha. Extracellular inducers of NF-kappa B activate signal transduction pathways that result in the phosphorylation and subsequent degradation of I kappa B alpha. At present, the link between phosphorylation of I kappa B alpha and its degradation is not understood. In this report we provide evidence that phosphorylation of serine residues 32 and 36 of I kappa B alpha targets the protein to the ubiquitin-proteasome pathway. I kappa B alpha is ubiquitinated in vivo and in vitro following phosphorylation, and mutations that abolish phosphorylation and degradation of I kappa B alpha in vivo prevent ubiquitination in vitro. Ubiquitinated I kappa B alpha remains associated with NF-kappa B, and the bound I kappa B alpha is degraded by the 26S proteasome. Thus, ubiquitination provides a mechanistic link between phosphorylation and degradation of I kappa B alpha.