Defining the structure of the NF-ĸB pathway in human immune cells using quantitative proteomic data

Kok, F. O., Wang, H., Riedlova, P., Goodyear, C. S. and Carmody, R. J. (2021) Defining the structure of the NF-ĸB pathway in human immune cells using quantitative proteomic data. Cellular Signalling, 88, 110154. (doi: 10.1016/j.cellsig.2021.110154) (PMID:34562606)

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Abstract

The NF-ĸB transcription factor is a critical regulator of immune homeostasis and inflammatory responses and is a critical factor in the pathogenesis of inflammatory disease. The pathways to NF-ĸB activation are paradigms for signal-induced ubiquitination and proteasomal degradation, control of transcription factor function by subcellular localisation, and the control of gene transcription and physiological processes by signal transduction mechanisms. Despite the importance of NF-ĸB in disease, the NF-ĸB pathway remains unexploited for the treatment of inflammatory disease. Our understanding of NF-ĸB comes mostly from studies of transgenic mice and cell lines where components of the pathway have been deleted or over expressed. Recent advances in quantitative proteomics offer new opportunities to understand the NF-ĸB pathway using the absolute abundance of individual pathway components. We have analysed available quantitative proteomic datasets to establish the structure of the NF-ĸB pathway in human immune cells under both steady state and activated conditions. This reveals a conserved NF-κB pathway structure across different immune cell lineages and identifies important differences to the current model of the NF-ĸB pathway. These include the findings that the IKK complex in most cells is likely to consist predominantly of IKKβ homodimers, that the relative abundancies of IκB proteins show strong cell type variation, and that the components of the non-canonical NF-ĸB pathway are significantly increased in activated immune cells. These findings challenge aspects of our current view of the NF-κB pathway and identify outstanding questions important for defining the role of key components in regulating inflammation and immunity.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Kok, Dr Fatma and Riedlova, Ms Patricia and Carmody, Dr Ruaidhri and Goodyear, Professor Carl
Authors: Kok, F. O., Wang, H., Riedlova, P., Goodyear, C. S., and Carmody, R. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Cellular Signalling
Publisher:Elsevier
ISSN:0898-6568
ISSN (Online):1873-3913
Published Online:22 September 2021
Copyright Holders:Copyright © 2021 The Authors
First Published:First published in Cellular Signalling 88: 110154
Publisher Policy:Reproduced under a Creative Commons License

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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
306394A structure-function analysis of USP7 and NF-kB interaction.Ruaidhri CarmodyBiotechnology and Biological Sciences Research Council (BBSRC)BB/T007427/1III - Immunology