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dc.contributor.authorParkinson, Michael DJ
dc.contributor.authorPiper, Siân C
dc.contributor.authorBright, Nicholas
dc.contributor.authorEvans, Jennifer L
dc.contributor.authorBoname, Jessica M
dc.contributor.authorBowers, Katherine
dc.contributor.authorLehner, Paul
dc.contributor.authorLuzio, John
dc.date.accessioned2015-07-30T13:16:52Z
dc.date.available2015-07-30T13:16:52Z
dc.date.issued2015-10-01
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 Lys(63)-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 RNAi-mediated depletion of individual proteins of the ESCRT-0 and ESCRT-I complexes and three ESCRT-III proteins showed that these are required to down-regulate MHC class I. However, depletion of proteins of the ESCRT-II complex or of the ESCRT-III protein, VPS20 (vacuolar protein sorting 20)/CHMP6 (charged MVB protein 6), failed to prevent the loss of MHC class I from the cell surface. Depletion of histidine domain phosphotyrosine phosphatase (HD-PTP) 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 (WT) 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.languageEnglish
dc.language.isoen
dc.publisherPortland Press Ltd.
dc.rightsAttribution 2.0 UK: England & Wales
dc.rights.urihttp://creativecommons.org/licenses/by/2.0/uk/
dc.subjectendocytosis
dc.subjectendosomal sorting complex required for transport (ESCRT)
dc.subjectHis domain phosphotyrosine phosphatase (HD-PTP)
dc.subjectHis-Domain Type N23 protein tyrosine phosphatase (PTPN23)
dc.subjectlysosome
dc.subjectubiquitination (ubiquitylation)
dc.titleA non-canonical ESCRT pathway, including histidine domain phosphotyrosine phosphatase (HD-PTP), is used for down-regulation of virally ubiquitinated MHC class I.
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/BJ20150336
prism.endingPage88
prism.publicationDate2015
prism.publicationNameBiochem J
prism.startingPage79
prism.volume471
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.dateAccepted2015-07-28
rioxxterms.versionofrecord10.1042/BJ20150336
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2015-09-25
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/Review
pubs.funder-project-idMedical Research Council (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)
cam.issuedOnline2015-09-21


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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