HDAC1 interacts with the p50 NF-κB subunit via its nuclear localization sequence to constrain inflammatory gene expression

Cartwright, T. N., Worrell, J. C. , Marchetti, L., Dowling, C. M., Knox, A., Kiely, P., Mann, J., Mann, D. A. and Wilson, C. L. (2018) HDAC1 interacts with the p50 NF-κB subunit via its nuclear localization sequence to constrain inflammatory gene expression. Biochimica et Biophysica Acta: Gene Regulatory Mechanisms, 1861(10), pp. 962-970. (doi:10.1016/j.bbagrm.2018.09.001) (PMID:30496041)

Cartwright, T. N., Worrell, J. C. , Marchetti, L., Dowling, C. M., Knox, A., Kiely, P., Mann, J., Mann, D. A. and Wilson, C. L. (2018) HDAC1 interacts with the p50 NF-κB subunit via its nuclear localization sequence to constrain inflammatory gene expression. Biochimica et Biophysica Acta: Gene Regulatory Mechanisms, 1861(10), pp. 962-970. (doi:10.1016/j.bbagrm.2018.09.001) (PMID:30496041)

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Abstract

The NF-κB p50 subunit is an important regulator of inflammation, with recent experimental evidence to support it also having a tumor suppressor role. Classically, p50 functions in heterodimeric form with the RelA (p65) NF-κB subunit to activate inflammatory genes. However, p50 also forms homodimers which actively repress NF-κB-dependent inflammatory gene expression and exert an important brake on the inflammatory process. This repressive activity of p50:p50 is thought to be in part mediated by an interaction with the epigenetic repressor protein Histone Deacetylase 1 (HDAC1). However, neither the interaction of p50 with HDAC1 nor the requirement of HDAC1 for the repressive activities of p50 has been well defined. Here we employed in silico prediction with in vitro assays to map sites of interaction of HDAC1 on the p50 protein. Directed mutagenesis of one such region resulted in almost complete loss of HDAC1 binding to p50. Transfected mutant p50 protein lacking the putative HDAC1 docking motif resulted in enhanced cytokine and chemokine expression when compared with cells expressing a transfected wild type p50. In addition, expression of this mutant p50 was associated with enhanced chemoattraction of neutrophils and acetylation of known inflammatory genes demonstrating the likely importance of the p50:HDAC1 interaction for controlling inflammation. These new insights provide an advance on current knowledge of the mechanisms by which NF-κB-dependent gene transcription are regulated and highlight the potential for manipulation of p50:HDAC1 interactions to bring about experimental modulation of chronic inflammation and pathologies associated with dysregulated neutrophil accumulation and activation.

Item Type:Articles
Additional Information:The authors would like to thank their colleagues in the NFRG for their technical assistance and Prof. Neil Perkins for the provision of WT p50-FLAG pcDNA3.1 constructs. This work was supported by grants received from the Irish Cancer Society Grant (CRS12DOW), Science Foundation Ireland Grant (12/RI/2345) [P.K]. This work was also funded by Cancer Research UK Grant (C18342/A2390) and Medical Research Council Grant (MR/K001949) [D.A.M.].
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Worrell, Dr Julie
Authors: Cartwright, T. N., Worrell, J. C., Marchetti, L., Dowling, C. M., Knox, A., Kiely, P., Mann, J., Mann, D. A., and Wilson, C. L.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Biochimica et Biophysica Acta: Gene Regulatory Mechanisms
Publisher:Elsevier
ISSN:1874-9399
ISSN (Online):1874-9399
Published Online:10 September 2018
Copyright Holders:Copyright © 2018 Crown Copyright
First Published:First published in Biochimica et Biophysica Acta: Gene Regulatory Mechanisms 1861(10):962-970
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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