Collins, P. E., Grassia, G., Colleran, A., Kiely, P. A., Ialenti, A., Maffia, P. and Carmody, R. J. (2015) Mapping the interaction of B cell Leukemia 3 (BCL-3) and nuclear factor κB (NF-κB) p50 identifies a BCL-3-mimetic anti-inflammatory peptide. Journal of Biological Chemistry, 290(25), pp. 15687-15696. (doi: 10.1074/jbc.M115.643700) (PMID:25922067) (PMCID:PMC4505479)
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Abstract
The NF-κB transcriptional response is tightly regulated by a number of processes including the phosphorylation, ubiquitination, and subsequent proteasomal degradation of NF-κB subunits. The IκB family protein BCL-3 stabilizes a NF-κB p50 homodimer·DNA complex through inhibition of p50 ubiquitination. This complex inhibits the binding of the transcriptionally active NF-κB subunits p65 and c-Rel on the promoters of NF-κB target genes and functions to suppress inflammatory gene expression. We have previously shown that the direct interaction between p50 and BCL-3 is required for BCL-3-mediated inhibition of pro-inflammatory gene expression. In this study we have used immobilized peptide array technology to define regions of BCl-3 that mediate interaction with p50 homodimers. Our data show that BCL-3 makes extensive contacts with p50 homodimers and in particular with ankyrin repeats (ANK) 1, 6, and 7, and the N-terminal region of Bcl-3. Using these data we have designed a BCL-3 mimetic peptide based on a region of the ANK1 of BCL-3 that interacts with p50 and shares low sequence similarity with other IκB proteins. When fused to a cargo carrying peptide sequence this BCL-3-derived peptide, but not a mutated peptide, inhibited Toll-like receptor-induced cytokine expression in vitro. The BCL-3 mimetic peptide was also effective in preventing inflammation in vivo in the carrageenan-induced paw edema mouse model. This study demonstrates that therapeutic strategies aimed at mimicking the functional activity of BCL-3 may be effective in the treatment of inflammatory disease.
Item Type: | Articles |
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Status: | Published |
Refereed: | Yes |
Glasgow Author(s) Enlighten ID: | Maffia, Professor Pasquale and Grassia, Dr Gianluca and Carmody, Dr Ruaidhri and Collins, Ms Patricia |
Authors: | Collins, P. E., Grassia, G., Colleran, A., Kiely, P. A., Ialenti, A., Maffia, P., and Carmody, R. J. |
College/School: | College of Medical Veterinary and Life Sciences > School of Infection & Immunity |
Journal Name: | Journal of Biological Chemistry |
Publisher: | American Society for Biochemistry and Molecular Biology, Inc. |
ISSN: | 0021-9258 |
ISSN (Online): | 1083-351X |
Published Online: | 28 April 2015 |
Copyright Holders: | Copyright © 2015 The American Society for Biochemistry and Molecular Biology, Inc. |
First Published: | First published in Journal of Biological Chemistry 290(25): 15687-15696 |
Publisher Policy: | Reproduced in accordance with the publisher copyright policy |
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