An investigation into the role of Bcl-3 in toll-like receptor signalling
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Date
2014
Authors
Collins, Patricia E.
Journal Title
Journal ISSN
Volume Title
Publisher
University College Cork
Published Version
Abstract
Through the recognition of potentially harmful stimuli, Toll-like receptors (TLRs)
initiate the innate immune response and induce the expression of hundreds of
immune and pro-inflammatory genes. TLRs are critical in mounting a defence
against invading pathogens however, strict control of TLR signalling is vital to
prevent host damage from excessive or prolonged immune activation. In this thesis
the role of the IκB protein Bcl (B-cell lymphoma)-3 in the regulation of TLR
signalling is investigated. Bcl3-/- mice and cells are hyper responsive to TLR
stimulation and are defective in LPS tolerance. Bcl-3 interacts with and blocks the
ubiquitination of homodimers of the NF-κB subunit, p50. Through stabilisation of
inhibitory p50 homodimers, Bcl-3 negatively regulates NF-κB dependent
inflammatory gene transcription following TLR activation. Firstly, we investigated
the nature of the interaction between Bcl-3 and p50 and using peptide array
technology. Key amino acids required for the formation of the p50:Bcl-3
immunosuppressor complex were identified. Furthermore, we demonstrate for the
first time that interaction between Bcl-3 and p50 is necessary and sufficient for the
anti-inflammatory properties of Bcl-3. Using the data generated from peptide array
analysis we then generated cell permeable peptides designed to mimic Bcl-3
function and stabilise p50 homodimers. These Bcl-3 derived peptides are potent
inhibitors of NF-κB dependent transcription activity in vitro and provide a solid basis
for the development of novel gene-specific approaches in the treatment of
inflammatory diseases. Secondly, we demonstrate that Bcl-3 mediated regulation
of TLR signalling is not limited to NF-κB and identify the MAK3K Tumour Progression
Locus (Tpl)-2 as a new binding partner of Bcl-3. Our data establishes role for Bcl-3
as a negative regulator of the MAPK-ERK pathway.
Description
Keywords
NF-kB , Ubiquitination , Inflammation , Bcl-3
Citation
Collins, P. E. An investigation into the role of Bcl-3 in toll-like receptor signalling. PhD Thesis, University College Cork.