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

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dc.check.embargoformatE-thesis on CORA onlyen
dc.check.entireThesisEntire Thesis Restricted
dc.check.opt-outNot applicableen
dc.check.reasonThis thesis is due for publication or the author is actively seeking to publish this materialen
dc.contributor.advisorMcCarthy, Justin V.en
dc.contributor.authorYan, Run
dc.contributor.funderIrish Research Council for Science Engineering and Technologyen
dc.contributor.funderScience Foundation Irelanden
dc.date.accessioned2013-07-17T08:53:54Z
dc.date.issued2013
dc.date.submitted2013
dc.description.abstractPost-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.sponsorshipIrish 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.description.statusNot peer revieweden
dc.description.versionAccepted Version
dc.format.mimetypeapplication/pdfen
dc.identifier.citationYan, R. 2013. Characterization of TRAF6 mediated ubiquitination of presenilins and γ-secretase substrates. PhD Thesis, University College Cork.en
dc.identifier.endpage197
dc.identifier.urihttps://hdl.handle.net/10468/1183
dc.language.isoenen
dc.publisherUniversity College Corken
dc.rights© 2013, Run Yan.en
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/en
dc.subjectPresenilinen
dc.subjectGamma-secretaseen
dc.subjectTRAF6en
dc.subjectUbiquitinationen
dc.subjectRegulated intramembrane proteolysisen
dc.subject.lcshProteolytic enzymesen
dc.subject.lcshProteinsen
dc.thesis.opt-outfalse*
dc.titleCharacterization of TRAF6 mediated ubiquitination of presenilins and γ-secretase substratesen
dc.typeDoctoral thesisen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD (Science)en
ucc.workflow.supervisorcora@ucc.ie*
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