Inhibition of ubiquitin-proteasome pathway-mediated IκBα degradation by a naturally occurring antibacterial peptide

Youhe Gao, Stewart Lecker, Mark J. Post, Antti J. Hietaranta, Jian Li, Rudiger Volk, Min Li, Kaori Sato, Ashok K. Saluja, Michael L. Steer, Alfred L. Goldberg, Michael Simons

Research output: Contribution to journalArticle

147 Scopus citations

Abstract

Induction of NF-κB-dependent gene expression plays an important role in a number of biological processes including inflammation and ischemia-reperfusion 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 α7 subunit of the 26S proteasome and blocks degradation of NF-κB inhibitor IκBα by the ubiquitin-proteasome pathway without affecting overall proteasome activity. IκBα phosphorylation and ubiquitination occur normally after PR39 treatment, and binding of valosin-containing proteins is not impaired. The inhibition of IκBα degradation abolishes induction ofNF-κB-dependent gene expression in cell culture and in mouse models of acute pancreatitis and myocardial infarction, including upregulation of endothelial adhesion proteins VCAM- 1 and ICAM-1. In the latter model, sustained infusion of PR39 peptide resulted in significant reduction of myocardial infarct size. PR39 and related peptides may provide novel means to regulate cellular function and to control of NF-κB-dependent gene expression for therapeutic purposes.

Original languageEnglish (US)
Pages (from-to)439-448
Number of pages10
JournalJournal of Clinical Investigation
Volume106
Issue number3
DOIs
StatePublished - 2000

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