SUMO-1 modification of IκBα inhibits NF-κB activation

Activation of NF-kappa B is achieved by ubiquitination and proteasome-mediated degradation of I kappa B alpha. We have detected modified I kappa B alpha, conjugated to the small ubiquitin-like protein SUMO-1,which is resistant to signal-induced degradation. In the presence of an El SUMO-1-activating enzyme, Ubch9 conjugated SUMO-1 to I kappa B alpha primarily on K21,which is also utilized for ubiquitin modification. Thus, SUMO-1-modified I kappa B alpha cannot be ubiquitinated and is resistant to proteasome-mediated degradation. As a result, overexpression of SUMO-1 inhibits signal-induced activation of NF-kappa B-dependent transcription. Unlike ubiquitin modification, which requires phosphorylation of S32 and S36, SUMO-1 modification of I kappa B alpha is inhibited by phosphorylation. Thus, while ubiquitination targets proteins for rapid degradation, SUMO-1 modification acts antagonistically to generate proteins resistant to degradation.