Characterization of the degradation of wild-type and mutant HFE proteins during stress signalling in the endoplasmic reticulum

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dc.check.date10000-01-01
dc.check.embargoformatBoth hard copy thesis and e-thesisen
dc.check.entireThesisEntire Thesis Restricted
dc.check.infoIndefiniteen
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.advisorFleming, John V.en
dc.contributor.authorFoley, Louise Aileen
dc.contributor.funderIrish Research Council for Science Engineering and Technologyen
dc.date.accessioned2015-08-19T15:05:13Z
dc.date.issued2014
dc.date.submitted2014
dc.description.abstractHFE is a transmembrane protein that becomes N-glycosylated during transport to the cell membrane. It acts to regulate cellular iron uptake by interacting with the Type 1 transferrin receptor and interfering with its ability to bind iron-loaded transferrin. There is also evidence that HFE regulates systemic iron levels by binding to the Type II transferrin receptor although the mechanism by which this occurs is still not well understood. Mutations to HFE that disrupt this function, or physiological conditions that decrease HFE protein levels, are associated with increased iron uptake, and its accumulation in tissues and organs. This is exemplified by the point mutation that results in conversion of cysteine residue 282 to tyrosine (C282Y), and gives rise to the majority of HFE-related hemochromatoses. The C282Y mutation prevents the formation of a disulfide bridge and disrupts the interaction with its co-chaperone β2-microglobulin. The resulting misfolded protein is retained within the endoplasmic reticulum (ER) where it activates the Unfolded Protein Response (UPR) and is subjected to proteasomal degradation. The absence of functional HFE at the cell surface leads to unregulated iron uptake and iron loading. While the E3 ubiquitin ligase involved in the degradation of HFE-C282Y has been identified, the mechanism by which it is targeted for degradation remains relatively obscure. The primary objective of this project was to further our understanding of how the iron regulatory HFE protein is targeted for degradation. Our studies suggest that the glycosylation status, and the active process of deglycosylation, are central to this process. We identified a number of additional factors that can contribute towards degradation and explored their regulation during ER stress conditions.en
dc.description.sponsorshipIrish Research Council for Science Engineering and Technology (EMBARK initiative)en
dc.description.statusNot peer revieweden
dc.description.versionAccepted Version
dc.format.mimetypeapplication/pdfen
dc.identifier.citationFoley, L. A. 2014. Characterization of the degradation of wild-type and mutant HFE proteins during stress signalling in the endoplasmic reticulum. PhD Thesis, University College Cork.en
dc.identifier.urihttps://hdl.handle.net/10468/1926
dc.language.isoenen
dc.publisherUniversity College Corken
dc.rights© 2014, Louise A. Foleyen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/en
dc.subjectGlycosylationen
dc.subjectendoplasmic reticulumen
dc.subjectIron uptakeen
dc.subjectStress signallingen
dc.subjectUnfolded protein responseen
dc.subjectEndoplasmic reticulumen
dc.thesis.opt-outfalse
dc.titleCharacterization of the degradation of wild-type and mutant HFE proteins during stress signalling in the endoplasmic reticulumen
dc.typeDoctoral thesisen
dc.type.qualificationlevelDoctoral Degree (Structured)en
dc.type.qualificationnamePhD (Science)en
ucc.workflow.supervisorj.fleming@ucc.ie
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