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dc.contributor.authorParkinson, Michael DJen
dc.contributor.authorPiper, Siân Cen
dc.contributor.authorBright, Nicholasen
dc.contributor.authorEvans, Jennifer Len
dc.contributor.authorBoname, Jessica Men
dc.contributor.authorBowers, Katherineen
dc.contributor.authorLehner, Paulen
dc.contributor.authorLuzio, Johnen
dc.date.accessioned2015-07-30T13:16:52Z
dc.date.available2015-07-30T13:16:52Z
dc.date.issued2015-09-25en
dc.identifier.citationParkinson et al. Biochemical Journal (2015) Vol. 471, Issue 1, pp. 79-88. DOI: 10.1042/BJ20150336
dc.identifier.issn0264-6021
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/249129
dc.description.abstractThe Kaposi’s sarcoma-associated herpes virus (KSHV) K3 viral gene product effectively down-regulates cell surface MHC Class I. K3 is an E3 ubiquitin ligase that promotes K63-linked polyubiquitination of MHC Class I, providing the signal for clathrin mediated endocytosis. Endocytosis is followed by sorting into the intralumenal vesicles (ILVs) of multivesicular bodies (MVBs) and eventual delivery to lysosomes. The sorting of MHC Class I into MVBs requires many individual proteins of the four endosomal sorting complexes required for transport (ESCRTs). In HeLa cells expressing the KSHV K3 ubiquitin ligase, the effect of RNA interference-mediated depletion of individual proteins of the ESCRT-0 and ESCRT-I complexes and three ESCRT-III proteins showed that these are required to downregulate MHC Class I. However, depletion of proteins of the ESCRT-II complex or of the ESCRT-III protein, VPS20/CHMP6, failed to prevent the loss of MHC Class I from the cell surface. Depletion of His domain phosphotyrosine phosphatase (HDPTP) resulted in an increase in the cell surface concentration of MHC Class I in HeLa cells expressing the KSHV K3 ubiquitin ligase. Rescue experiments with wild type and mutant HD-PTP supported the conclusion that HD-PTP acts as an alternative to ESCRT-II and VPS20/CHMP6 as a link between the ESCRT-I and those ESCRT-III protein(s) necessary for ILV formation. Thus, the down-regulation of cell surface MHC Class I, polyubiquitinated by the KSHV K3 ubiquitin ligase, does not employ the canonical ESCRT pathway, but instead utilizes an alternative pathway in which HD-PTP replaces ESCRT-II and VPS20/CHMP6.
dc.description.sponsorshipThis work was supported by an MRC research grant to J.P.L. (G0900113). M.D.J.P. and J.L.E. were MRC research students and S.P. a Wellcome Trust research student. K.B. was a British Heart Foundation Intermediate Fellow and P.J.L. is a Wellcome Trust Principal Fellow. The CIMR is supported by a Wellcome Trust Strategic Award 100140 and an electron microscope was purchased with Wellcome Trust grant 093026.
dc.languageEnglishen
dc.language.isoenen
dc.publisherPortland Press
dc.rightsAttribution 2.0 UK: England & Wales
dc.rights.urihttp://creativecommons.org/licenses/by/2.0/uk/
dc.subjectendocytosisen
dc.subjectendosomal sorting complex required for transport (ESCRT)en
dc.subjectHis domain phosphotyrosine phosphatase (HD-PTP)en
dc.subjectHis-Domain Type N23 protein tyrosine phosphatase (PTPN23)en
dc.subjectlysosomeen
dc.subjectubiquitination (ubiquitylation)en
dc.titleA non-canonical ESCRT pathway, including His domain phosphotyrosine phosphatase (HD-PTP), is used for down-regulation of virally ubiquitinated MHC Class Ien
dc.typeArticle
dc.description.versionThis is the final version of the article. It first appeared from Portland Press via http://dx.doi.org/10.1042/BJ20150336en
prism.endingPage88
prism.publicationDate2015en
prism.publicationNameBiochemical Journalen
prism.startingPage79
prism.volume471en
dc.rioxxterms.funderMRC
dc.rioxxterms.funderWellcome Trust
dc.rioxxterms.funderWellcome Trust
dc.rioxxterms.funderBHF
dc.rioxxterms.projectidG0900113
dc.rioxxterms.projectidStrategic Award 100140
dc.rioxxterms.projectidGrant 093026
dcterms.dateAccepted2015-07-28en
rioxxterms.versionofrecord10.1042/BJ20150336en
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2015-09-25en
dc.contributor.orcidBright, Nicholas [0000-0002-2791-6727]
dc.contributor.orcidLehner, Paul [0000-0001-9383-1054]
dc.contributor.orcidLuzio, John [0000-0003-3912-9760]
dc.identifier.eissn1470-8728
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idMRC (G0900113)
pubs.funder-project-idWellcome Trust (101835/Z/13/Z)
pubs.funder-project-idWellcome Trust (100140/Z/12/Z)
pubs.funder-project-idWellcome Trust (093026/Z/10/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