An investigation into the role of Bcl-3 in toll-like receptor signalling

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dc.check.embargoformatBoth hard copy thesis and e-thesisen
dc.check.entireThesisEntire Thesis Restricted
dc.check.opt-outNoen
dc.check.reasonThis thesis is due for publication or the author is actively seeking to publish this materialen
dc.contributor.advisorCarmody, Ruaidhrí J.en
dc.contributor.advisorO'Neill, Coraen
dc.contributor.authorCollins, Patricia E.
dc.contributor.funderScience Foundation Irelanden
dc.date.accessioned2015-08-19T12:22:16Z
dc.date.issued2014
dc.date.submitted2014
dc.description.abstractThrough 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.en
dc.description.sponsorshipScience Foundation Ireland (08/IN.1/B1843)en
dc.description.statusNot peer revieweden
dc.description.versionAccepted Version
dc.format.mimetypeapplication/pdfen
dc.identifier.citationCollins, P. E. An investigation into the role of Bcl-3 in toll-like receptor signalling. PhD Thesis, University College Cork.en
dc.identifier.endpage258
dc.identifier.urihttps://hdl.handle.net/10468/1923
dc.language.isoenen
dc.publisherUniversity College Corken
dc.rights© 2014, Patricia E. Collins.en
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/en
dc.subjectNF-kBen
dc.subjectUbiquitinationen
dc.subjectInflammationen
dc.subjectBcl-3en
dc.thesis.opt-outfalse
dc.titleAn investigation into the role of Bcl-3 in toll-like receptor signallingen
dc.typeDoctoral thesisen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD (Science)en
ucc.workflow.supervisorc.oneill@ucc.ie
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