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

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
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Maffia, Dr 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 > Institute of Infection Immunity and Inflammation
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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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
659831Dissecting the function of Bcl-3 in NF-kappaB signaling in B cellsRuaidhri CarmodyBiotechnology and Biological Sciences Research Council (BBSRC)BB/M003671/1RI INFECTION IMMUNITY & INFLAMMATION
644661In Situ Nanoparticle Assemblies for Healthcare Diagnostics and TherapyPasquale MaffiaEngineering & Physical Sciences Research Council (EPSRC)EP/L014165/1III -IMMUNOLOGY