Inhibition of ubiquitin-proteasome pathway-mediated I kappa B alpha degradation by a naturally occurring antibacterial peptide

Induction of NF-kappa B-dependent gene expression plays an important role i n a number of biological processes including inflammation and ischemia-repe rfusion injury. However, few attempts aimed at selective regulation of this transcription factor have been successful. We report here that a naturally occurring antibacterial peptide PR39 reversibly binds to the alpha 7 subun it of the 26S proteasome and blocks degradation of NF-kappa B inhibitor I k appa B alpha by the ubiquitin-proteasome pathway without affecting overall proteasome activity. I kappa B alpha phosphorylation and ubiquitination occ ur normally after PR39 treatment, and binding of valosin-containing protein s is not impaired, The inhibition of I kappa B alpha degradation abolishes induction of NF-kappa B-dependent gene expression in cell culture and in mo use models of acute pancreatitis and myocardial infarction, including upreg ulation of endothelial adhesion proteins VCAM-1 and ICAM-1. In the latter m odel, sustained infusion of PR39 peptide resulted in significant reduction of myocardial infarct size. PR39 and related peptides may provide novel mea ns to regulate cellular function and to control of NF-kappa B-dependent gen e expression for therapeutic purposes.