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

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dc.contributor.advisor Fleming, John V. en
dc.contributor.author Foley, Louise Aileen
dc.date.accessioned 2015-08-19T15:05:13Z
dc.date.issued 2014
dc.date.submitted 2014
dc.identifier.citation Foley, 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.uri http://hdl.handle.net/10468/1926
dc.description.abstract HFE 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.sponsorship Irish Research Council for Science Engineering and Technology (EMBARK initiative) en
dc.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher University College Cork en
dc.rights © 2014, Louise A. Foley en
dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/3.0/ en
dc.subject Glycosylation en
dc.subject endoplasmic reticulum en
dc.subject Iron uptake en
dc.subject Stress signalling en
dc.subject Unfolded protein response en
dc.subject Endoplasmic reticulum en
dc.title Characterization of the degradation of wild-type and mutant HFE proteins during stress signalling in the endoplasmic reticulum en
dc.type Doctoral thesis en
dc.type.qualificationlevel Doctoral Degree (Structured) en
dc.type.qualificationname PhD (Science) en
dc.internal.availability Full text not available en
dc.check.info Indefinite en
dc.check.date 10000-01-01
dc.description.version Accepted Version
dc.contributor.funder Irish Research Council for Science Engineering and Technology en
dc.description.status Not peer reviewed en
dc.internal.school 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 Both hard copy thesis and e-thesis en
ucc.workflow.supervisor j.fleming@ucc.ie
dc.internal.conferring Autumn Conferring 2014


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© 2014, Louise A. Foley Except where otherwise noted, this item's license is described as © 2014, Louise A. Foley
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