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Title: Mapping the ubiquitin ligase interaction landscape at the endoplasmic reticulum membrane
Author: Fenech, Emma
ISNI:       0000 0004 7653 7779
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2018
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The Endoplasmic Reticulum (ER) is the entry-point of the secretory pathway and is responsible for coordinating essential cellular functions, including ER-associated degradation, calcium flux and sterol homeostasis. These processes are regulated by a common post-translational mechanism: the ubiquitination of target substrates by RING-domain E3 ubiquitin ligases (E3s) resident in the ER membrane. At least 25 different transmembrane domain-containing E3s are reported to be ER-localised. However, despite the indication that select E3s control specific ER and cellular functions, few have been extensively characterised. Since E3 function is determined by the complexes it forms with specific cofactors, as well as interactions with the substrates it regulates, the primary objective of this project was to map the interaction networks of these E3 ligases. To this aim, mass spectrometry coupled with comparative proteomic profiling was employed to identify high-confidence interacting proteins (HCIPs) for the ER-resident E3 family. Using this approach, 226 HCIPs were discovered for 21 E3s, which represent novel potential cofactors and substrates, and implicate the ER-resident E3s in multiple homeostatic, metabolic and regulatory processes. A subset of HCIPs were validated as bona fide E3 interactors, including the RNF26 interactors TMEM43, TMED1 and ENDOD1. These largely uncharacterised membrane-embedded proteins were found to contribute to the role of RNF26 in regulating STING-dependent innate immune signalling, which orchestrates a protective response against pathogenic DNA viruses. Therefore, these data provide a comprehensive collection of E3 interaction networks at the ER membrane, which serves as a discovery platform to enable the characterisation of ER-resident E3 complexes and their functions.
Supervisor: Christianson, John Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available