The regulation of sequence specific NF-ĸB DNA binding and transcription by IKKβ Phosphorylation of NF-ĸB p50 at Serine 80

Smith, E. L., Somma, D., Kerrigan, D., McIntyre, Z., Cole, J. J., Liang, K. L., Kiely, P. A., Keeshan, K. and Carmody, R. J. (2019) The regulation of sequence specific NF-ĸB DNA binding and transcription by IKKβ Phosphorylation of NF-ĸB p50 at Serine 80. Nucleic Acids Research, 47(21), pp. 11151-11161. (doi: 10.1093/nar/gkz873) (PMID:31598684) (PMCID:PMC6868378)

[img]
Preview
Text
199208.pdf - Published Version
Available under License Creative Commons Attribution.

3MB

Abstract

Phosphorylation of the NF-κB transcription factor is an important regulatory mechanism for the control of transcription. Here we identify serine 80 (S80) as a phosphorylation site on the p50 subunit of NF-κB, and IKKβ as a p50 kinase. Transcriptomic analysis of cells expressing a p50 S80A mutant reveals a critical role for S80 in selectively regulating the TNFα inducible expression of a subset of NF-κB target genes including pro-inflammatory cytokines and chemokines. S80 phosphorylation regulates the binding of p50 to NF-κB binding (κB) sites in a sequence specific manner. Specifically, phosphorylation of S80 reduces the binding of p50 at κB sites with an adenine at the −1 position. Our analyses demonstrate that p50 S80 phosphorylation predominantly regulates transcription through the p50:p65 heterodimer, where S80 phosphorylation acts in trans to limit the NF-κB mediated transcription of pro-inflammatory genes. The regulation of a functional class of pro-inflammatory genes by the interaction of S80 phosphorylated p50 with a specific κB sequence describes a novel mechanism for the control of cytokine-induced transcriptional responses.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:SMITH, Emma and Cole, Mr John and Kerrigan, Mr David and Carmody, Dr Ruaidhri and Keeshan, Dr Karen and Somma, Domenico
Authors: Smith, E. L., Somma, D., Kerrigan, D., McIntyre, Z., Cole, J. J., Liang, K. L., Kiely, P. A., Keeshan, K., and Carmody, R. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Nucleic Acids Research
Publisher:Oxford University Press
ISSN:0305-1048
ISSN (Online):1362-4962
Published Online:10 October 2019
Copyright Holders:Copyright © 2019 The Authors
First Published:First published in Nucleic Acids Research 47(21):11151-11161
Publisher Policy:Reproduced under a Creative Commons License

University Staff: Request a correction | Enlighten Editors: Update this record

Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
190848Investigating NF-kB p50 phosphorylation and the regulation of transcriptionRuaidhri CarmodyMedical Research Council (MRC)MR/M010694/1III - Immunology
190815Dissecting the function of Bcl-3 in NF-kappaB signaling in B cellsRuaidhri CarmodyBiotechnology and Biological Sciences Research Council (BBSRC)BB/M003671/1III - Immunology
190659BBSRC Doctoral Training Partnership 2012Jeremy MottramBiotechnology and Biological Sciences Research Council (BBSRC)BB/J013854/1MVLS - Graduate School