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dc.contributor.authorStefanovic-Barrett, Sandraen
dc.contributor.authorDickson, Annaen
dc.contributor.authorBurr, Stephenen
dc.contributor.authorWilliamson, Jamesen
dc.contributor.authorLobb, Ian Ten
dc.contributor.authorVan Den Boomen, Dicken
dc.contributor.authorLehner, Paulen
dc.contributor.authorNathan, Jamesen
dc.date.accessioned2018-05-02T16:14:12Z
dc.date.available2018-05-02T16:14:12Z
dc.date.issued2018-05en
dc.identifier.issn1469-221X
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/275453
dc.description.abstractMisfolded or damaged proteins are typically targeted for destruction by proteasome-mediated degradation, but the mammalian ubiquitin machinery involved is incompletely understood. Here, using forward genetic screens in human cells we find that the proteasome-mediated degradation of the soluble misfolded reporter, mCherry-CL1, involves two ER-resident E3 ligases, MARCH6 and TRC8. MCherry-CL1 degradation is routed via the ER membrane and dependent on the hydrophobicity of the substrate, with complete stabilisation only observed in double knockout MARCH6/TRC8 cells. To identify a more physiological correlate we used quantitative mass spectrometry and found that TRC8 and MARCH6 depletion altered the turnover of the tail-anchored protein Heme-Oxygenase-1 (HO-1). These E3 ligases associate with the intramembrane cleaving Signal Peptide Peptidase (SPP), and facilitate the degradation of HO-1 following intramembrane proteolysis. Our results highlight how ER-resident ligases may target the same substrates, but work independently of each other, to optimise the protein quality control of selected soluble and tail-anchored proteins.
dc.format.mediumPrint-Electronicen
dc.languageengen
dc.publisherWiley-Blackwell
dc.rightsAttribution 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.subjectHela Cellsen
dc.subjectEndoplasmic Reticulumen
dc.subjectHumansen
dc.subjectUbiquitin-Protein Ligasesen
dc.subjectMembrane Proteinsen
dc.subjectReceptors, Cell Surfaceen
dc.subjectHeme Oxygenase-1en
dc.subjectMass Spectrometryen
dc.subjectUbiquitinationen
dc.subjectGene Knockout Techniquesen
dc.subjectProteolysisen
dc.titleMARCH6 and TRC8 facilitate the quality control of cytosolic and tail-anchored proteins.en
dc.typeArticle
prism.issueIdentifier5en
prism.publicationDate2018en
prism.publicationNameEMBO reportsen
prism.volume19en
dc.identifier.doi10.17863/CAM.22673
dcterms.dateAccepted2018-02-15en
rioxxterms.versionofrecord10.15252/embr.201745603en
rioxxterms.versionVoR*
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2018-05en
dc.contributor.orcidDickson, Anna [0000-0001-6431-586X]
dc.contributor.orcidBurr, Stephen [0000-0001-8865-126X]
dc.contributor.orcidWilliamson, James [0000-0002-2009-189X]
dc.contributor.orcidVan Den Boomen, Dick [0000-0001-6474-3661]
dc.contributor.orcidLehner, Paul [0000-0001-9383-1054]
dc.contributor.orcidNathan, James Alexander [0000-0002-0248-1632]
dc.identifier.eissn1469-3178
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idWellcome Trust (102770/Z/13/Z)
pubs.funder-project-idWellcome Trust (101835/Z/13/Z)
pubs.funder-project-idMRC (1625900)
pubs.funder-project-idWellcome Trust (084957/Z/08/Z)
pubs.funder-project-idWellcome Trust (100140/Z/12/Z)
cam.orpheus.successThu Jan 30 12:58:59 GMT 2020 - The item has an open VoR version.*
rioxxterms.freetoread.startdate2100-01-01


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International