Characterization of TRAF6 mediated ubiquitination of presenilins and γ-secretase substrates

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dc.contributor.advisor McCarthy, Justin V. en Yan, Run 2013-07-17T08:53:54Z 2013 2013
dc.identifier.citation Yan, R. 2013. Characterization of TRAF6 mediated ubiquitination of presenilins and γ-secretase substrates. PhD Thesis, University College Cork. en
dc.identifier.endpage 197
dc.description.abstract Post-translational modification of the γ-secretase protease complexes and their substrates has an important role in controlling receptor-initiated signalling events, which are critically important in the pathogenesis of cancer, inflammatory and Alzheimer’s disease. Our lab has previously characterised an interaction between TRAF6 and presenilin-1, which lead to the identification of interleukin-1 (IL-1) receptor type 1 (IL-1R1) and Toll-like receptor-4 (TLR4) as novel γ-secretase substrates. Subsequently our group showed that TRAF6 promoted ubiquitination and γ-secretase cleavage of IL-1R1. The aim of this project is to study the association between TRAF6 and the presenilins, the critical γ-secretase complex components, and to determine the functional importance of TRAF6-mediated ubiquitination of γ-secretase substrates. Firstly, we show that the full-length presenilins are novel substrates of TRAF6-mediated Lysine-63-linked polyubiquitination. Secondly, we show that co-expression of TRAF6 and the presenilins increases the stability and alters the turnover of the presenilins. Thirdly, we reveal that TRAF6-mediated ubiquitination of presenilin does not affect γ-secretase enzyme activity, but may regulate the full-length presenilin functions such as ER Ca2+ signalling. Previously, we have reported IL-1R1 as a novel substrate of TRAF6-mediated ubiquitination. In this study, we identified five lysine residues in the IL-1R1 intracellular domain targeted by TRAF6-mediated polyubiquitination. Furthermore, mutagenesis of these five lysine residues led to decreased IL-1R1 cell surface expression, precluded the ectodomain shedding and attenuated the responsiveness to IL-1β stimulation, demonstrating the critical role of TRAF6 in IL-1R1 trafficking. en
dc.description.sponsorship Irish Research Council for Science Engineering and Technology (RS/2009/1245); Science Foundation Ireland (02/IN1/B218); Science Foundation Ireland (09/IN.1/B2624) en
dc.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher University College Cork en
dc.rights © 2013, Run Yan. en
dc.rights.uri en
dc.subject Presenilin en
dc.subject Gamma-secretase en
dc.subject TRAF6 en
dc.subject Ubiquitination en
dc.subject Regulated intramembrane proteolysis en
dc.subject.lcsh Proteolytic enzymes en
dc.subject.lcsh Proteins en
dc.title Characterization of TRAF6 mediated ubiquitination of presenilins and γ-secretase substrates en
dc.type Doctoral thesis en
dc.type.qualificationlevel Doctoral en
dc.type.qualificationname PhD (Science) en
dc.internal.availability Full text available en
dc.description.version Accepted Version
dc.contributor.funder Irish Research Council for Science Engineering and Technology en
dc.contributor.funder Science Foundation Ireland en
dc.description.status Not peer reviewed en Biochemistry en
dc.check.reason This thesis is due for publication or the author is actively seeking to publish this material en
dc.check.opt-out Not applicable en
dc.thesis.opt-out false *
dc.check.entireThesis Entire Thesis Restricted
dc.check.embargoformat E-thesis on CORA only en
ucc.workflow.supervisor *

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