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

Y Gao

S Lecker

M Post

A Hietaranta

A Saluja+3 authors

^{Angiogenesis Research Center, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA}^{Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA}^{Department of Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA}

Address correspondence to: Michael Simons, Angiogenesis Research Center, RW-453, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02215, USA. Phone: (617) 667-5364; Fax: (617) 975-5201; E-mail: ude.dravrah.puorgerac@snomism.

Received 2000 Mar 9; Accepted 2000 Jun 19.

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 of NF-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.

Abstract

Acknowledgments

We thank G. Walz for HA-ubiquitin plasmid construct MT123 and C.C. Li (NIH) for antiVCP-3 antibody.

This work was supported, in part, by the NIH grants HL-53793 and HL-56993 (M. Simons), DK-31396 (M.L. Steer), GM-51923 and GM-46147 (A.L. Goldberg), F32 HL-10013 (R. Volk); American Heart Association Established Investigator Award 9940074 (M. Simons); and a grant from Chiron Corporation.

Acknowledgments

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