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Control of NF-kB transcriptional activity by the IkappaB protein Bcl-3

Bcl-3 is an atypical IkappaB protein that is localised primarily in the nucleus where it selectively interacts with homodimers of the NF-kB p50 or p52 subunits. Bcl-3 plays a key role as a negative regulator of Toll-like receptor induced pro-inflammatory responses and is essential for promoting endotoxin tolerance in macrophages. Our previous work established Bcl-3 as an inhibitor of p50 homodimer ubiquitination and proteasomal degradation. Bcl-3 stabilises a DNA bound p50 homodimer complex which limits the expression of pro-inflammatory cytokines in macrophages.

The promoter binding of p50 homodimers is an important determinant of whether that gene will be repressed during endotoxin tolerance and selectively inhibits the expression of pro-inflammatory but not pro-resolution or anti-inflammatory genes. A biochemical mapping of the interaction interface between Bcl-3 and p50 homodimers allowed us to design a Bcl-3 mimetic peptide with potent anti-inflammatory activity both in vitro and in vivo. We are currently investigating the potential of targeting p50 homodimer stability as a means of selectively inhibiting pro-inflammatory transcriptional responses.

We are also investigating the role of Bcl-3 in regulating the non-canonical or alternative pathway of NF-kB. The non-canonical NF-kB pathway is activated by a restricted set of cell surface receptors which includes Lymphotoxin receptor, CD40 and BAFF receptor. Genetic models of Bcl3 deficiency reveal a phenotype associated with defective activation of the non-canonical pathway including defects in B cell survival and lymphoid organogenesis. Our reserach in this area is aimed at identifying the role of Bcl-3 in regulating the non-canonical pathway and defining the underlying molecular mechanisms.

These projects are funded by the Biotechnology and Biological Sciences Research Council and Arthritis Research UK.

Control of innate immune responses by phosphorylation of NF-kB p50

The NF-kB subunit p50, encoded by NFKB1, is the transcription factor most highly expressed in human macrophage and is a critical factor in human inflammatory disease. Functional polymorphisms in NFKB1 are significant risk factors for inflammatory disease and cancer. Phosphorylation of NF-kB is critically important for the transcription of target genes but a comprehensive analysis of p50 phosphorylation and its role in regulating transcription is notably lacking. We are generating a unique dataset of transcriptional events that are dependent on site-specific p50 phosphorylation, using a human macrophage model. We are using these datasets to developing a series of gene-expression signatures predictive of functional classes of p50 phosphorylation, the activity of the kinase responsible, and determine how these influence overall transcriptional responses in macrophages.

Existing transcriptomic data obtained from human macrophage or tissue from patients with inflammatory disease will be interrogated with our phospho-p50 specific transcriptomic signatures. This will allow us to generate a coexpression network model of p50 target genes regulated by site-specific phosphorylation. The network will integrate public data on chromatin modifications from human monocytes, macrophages and dendritic cells. The model will provide a powerful tool for the development of novel therapeutic strategies based on the regulation of gene expression by p50 phosphorylation. 


This project is funded by the Medical Research Council.

Investigating the regulation of NF-kB by the deubiquitinase USP7

The ubiquitination and proteasomal degradation of the NF-kB subunits is a critical regulatory mechansim which has a profound impact on NF-kB mediated transcriptional responses. The ubiquitination of NF-kB is triggered by DNA binding and is regulated by the phosphorylation and acetylation of NF-kB. A number of E3 ligases have been identified for NF-kB each of which contributes to the regulation of NF-kB transcriptional activity. The action of these E3 ligases on NF-kB is opposed by the deubiquitinase USP7 which promotes NF-kB stability and transcriptional activity. 

USP7 acts on a number of substrates and so our challenge is to understand how NF-kB is recongised as a substrate and how substrate specific inhition of USP7 can be achieved. The possibility of selectively inhibiting the deubiquitination of NF-kB offers the exciting possibiltiy of targeting only transcriptionally active NF-kB.

This project is currently funded by AstraZeneca through the GLAZgo Discovery Centre and previously by ARUK and MRC-T.

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