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 Saluja, Michael L. Steer, Alfred L. Goldberg, Michael Simons

Research output: Contribution to journalArticle

147 Citations (Scopus)

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 - Jan 1 2000
Externally publishedYes

Fingerprint

Proteasome Endopeptidase Complex
Ubiquitin
Gene Expression
Peptides
Myocardial Infarction
Biological Phenomena
Vascular Cell Adhesion Molecule-1
Ubiquitination
Intercellular Adhesion Molecule-1
Reperfusion Injury
Pancreatitis
Transcription Factors
Up-Regulation
Cell Culture Techniques
Phosphorylation
Inflammation
Proteins
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Inhibition of ubiquitin-proteasome pathway-mediated IκBα degradation by a naturally occurring antibacterial peptide. / Gao, Youhe; Lecker, Stewart; Post, Mark J.; Hietaranta, Antti J.; Li, Jian; Volk, Rudiger; Li, Min; Sato, Kaori; Saluja, Ashok; Steer, Michael L.; Goldberg, Alfred L.; Simons, Michael.

In: Journal of Clinical Investigation, Vol. 106, No. 3, 01.01.2000, p. 439-448.

Research output: Contribution to journalArticle

Gao, Y, Lecker, S, Post, MJ, Hietaranta, AJ, Li, J, Volk, R, Li, M, Sato, K, Saluja, A, Steer, ML, Goldberg, AL & Simons, M 2000, 'Inhibition of ubiquitin-proteasome pathway-mediated IκBα degradation by a naturally occurring antibacterial peptide', Journal of Clinical Investigation, vol. 106, no. 3, pp. 439-448. https://doi.org/10.1172/JCI9826
Gao, Youhe ; Lecker, Stewart ; Post, Mark J. ; Hietaranta, Antti J. ; Li, Jian ; Volk, Rudiger ; Li, Min ; Sato, Kaori ; Saluja, Ashok ; Steer, Michael L. ; Goldberg, Alfred L. ; Simons, Michael. / Inhibition of ubiquitin-proteasome pathway-mediated IκBα degradation by a naturally occurring antibacterial peptide. In: Journal of Clinical Investigation. 2000 ; Vol. 106, No. 3. pp. 439-448.
@article{2dd3796f74f348619240e9fe18d50efc,
title = "Inhibition of ubiquitin-proteasome pathway-mediated IκBα degradation by a naturally occurring antibacterial peptide",
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.",
author = "Youhe Gao and Stewart Lecker and Post, {Mark J.} and Hietaranta, {Antti J.} and Jian Li and Rudiger Volk and Min Li and Kaori Sato and Ashok Saluja and Steer, {Michael L.} and Goldberg, {Alfred L.} and Michael Simons",
year = "2000",
month = "1",
day = "1",
doi = "10.1172/JCI9826",
language = "English (US)",
volume = "106",
pages = "439--448",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "3",

}

TY - JOUR

T1 - Inhibition of ubiquitin-proteasome pathway-mediated IκBα degradation by a naturally occurring antibacterial peptide

AU - Gao, Youhe

AU - Lecker, Stewart

AU - Post, Mark J.

AU - Hietaranta, Antti J.

AU - Li, Jian

AU - Volk, Rudiger

AU - Li, Min

AU - Sato, Kaori

AU - Saluja, Ashok

AU - Steer, Michael L.

AU - Goldberg, Alfred L.

AU - Simons, Michael

PY - 2000/1/1

Y1 - 2000/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=0033847049&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0033847049&partnerID=8YFLogxK

U2 - 10.1172/JCI9826

DO - 10.1172/JCI9826

M3 - Article

VL - 106

SP - 439

EP - 448

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 3

ER -