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dc.contributor.authorvan, den Boomen DJHen
dc.contributor.authorLehner, Paulen
dc.date.accessioned2015-07-29T15:41:03Z
dc.date.available2015-07-29T15:41:03Z
dc.date.issued2015-07-22en
dc.identifier.citationMolecular Immunology 2015, 68(2A):106–111. doi: 10.1016/j.molimm.2015.07.005en
dc.identifier.issn0161-5890
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/249122
dc.description.abstractThe human cytomegalovirus (HCMV) US2 and US11 gene products hijack mammalian ER-associated degradation (ERAD) to induce rapid degradation of major histocompatibility class I (MHC-I) molecules. The rate-limiting step in this pathway is thought to be the polyubiquitination of MHC-I by distinct host ERAD E3 ubiquitin ligases. TRC8 was identified as the ligase responsible for US2-mediated MHC-I degradation and shown to be required for the cleavage-dependent degradation of some tail-anchored proteins. In addition to MHC-I, plasma membrane profiling identified further immune receptors, which are also substrates for the US2/TRC8 complex. These include at least six α integrins, the coagulation factor thrombomodulin and the NK cell ligand CD112. US2’s use of specific HCMV-encoded adaptors makes it an adaptable viral degradation hub. US11-mediated degradation is MHC-I-specific and genetic screens have identified TMEM129, an uncharacterised RING-C2 E3 ligase, as responsible for US11-mediated degradation. In a unique auto-regulatory loop, US11 readily responds to changes in cellular expression of MHC-I. Free US11 either rebinds more MHC-I or is itself degraded by the HRD1/SEL1L E3 ligase complex. While virally encoded US2 and US11 appropriate mammalian ERAD, the MHC-I complex also undergoes stringent cellular quality control and misfolded MHC-I is degraded by the HRD1/SEL1L complex. We discuss the identification and central role of E3 ubiquitin ligases in ER quality control and viral degradation of the MHC-I chain.
dc.description.sponsorshipThis study was financially supported by the Wellcome Trust (084957/Z/08/Z) and the Cambridge Biomedical Research Centre, UK.
dc.languageEnglishen
dc.language.isoenen
dc.publisherElsevier
dc.rightsAttribution 2.0 UK: England & Wales*
dc.rights.urihttp://creativecommons.org/licenses/by/2.0/uk/*
dc.subjectER-associated degradationen
dc.subjectE3 ubiquitin ligaseen
dc.subjectHuman cytomegalovirusen
dc.subjectViral immune evasionen
dc.subjectTRC8en
dc.subjectTMEM129en
dc.subjectHRD1en
dc.titleIdentifying the ERAD ubiquitin E3 ligases for viral and cellular targeting of MHC class Ien
dc.typeArticle
dc.description.versionThis is the final version. It was first published by Elsevier at http://dx.doi.org/10.1016/j.molimm.2015.07.005en
prism.endingPage111
prism.publicationDate2015en
prism.publicationNameMolecular Immunologyen
prism.startingPage106
prism.volume68en
dc.rioxxterms.funderWellcome Trust
dc.rioxxterms.funderBBSRC
dc.rioxxterms.projectid084957/Z/08/Z
dcterms.dateAccepted2015-07-06en
rioxxterms.versionofrecord10.1016/j.molimm.2015.07.005en
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2015-07-22en
dc.contributor.orcidLehner, Paul [0000-0001-9383-1054]
dc.identifier.eissn1872-9142
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idWellcome Trust (101835/Z/13/Z)
pubs.funder-project-idWellcome Trust (084957/Z/08/Z)
pubs.funder-project-idWellcome Trust (100140/Z/12/Z)


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Attribution 2.0 UK: England & Wales
Except where otherwise noted, this item's licence is described as Attribution 2.0 UK: England & Wales