Inhibition of ubiquitin-proteasome pathway-mediated I kappa B alpha degradation by a naturally occurring antibacterial peptide.
Induction of NF-kappaB-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 alpha 7 subunit of the 26S proteasome and blocks degradation of NF-kappa B inhibitor I kappa B alpha by the ubiquitin-proteasome pathway without affecting overall proteasome activity. I kappa B alpha phosphorylation and ubiquitination occur normally after PR39 treatment, and binding of valosin-containing proteins 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 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-kappa B-dependent gene expression for therapeutic purposes.
Angiogenesis Research Center, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
Y
Y
Gao
S
S
Lecker
M J
MJ
Post
A J
AJ
Hietaranta
J
J
Li
R
R
Volk
M
M
Li
K
K
Sato
A K
AK
Saluja
M L
ML
Steer
A L
AL
Goldberg
M
M
Simons
D000818:Animals; D000890:Anti-Infective Agents / Q000378:metabolism / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D020672:I-kappa B Proteins; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D009097:Multienzyme Complexes / Q000378:metabolism*; D009203:Myocardial Infarction / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D010195:Pancreatitis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex; D013552:Swine; D014452:Ubiquitins / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000890:Anti-Infective Agents; D023181:Antimicrobial Cationic Peptides; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D009097:Multienzyme Complexes; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D010455:Peptides; D014452:Ubiquitins; C072212:PR 39; D000072000:NF-KappaB Inhibitor alpha; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex