eprintid: 1470409 rev_number: 23 eprint_status: archive userid: 608 dir: disk0/01/47/04/09 datestamp: 2015-08-18 16:04:58 lastmod: 2021-10-10 23:09:48 status_changed: 2015-08-18 16:04:58 type: article metadata_visibility: show creators_name: Parkinson, MDJ creators_name: Piper, SC creators_name: Bright, NA creators_name: Evans, JL creators_name: Boname, JM creators_name: Bowers, K creators_name: Lehner, PJ creators_name: Luzio, JP title: A non-canonical ESCRT pathway, including His domain phosphotyrosine phosphatase (HD-PTP), is used for down-regulation of virally ubiquitinated MHC Class I ispublished: pub divisions: UCL divisions: B02 divisions: C08 divisions: D09 divisions: G03 divisions: B04 divisions: C05 divisions: F52 note: c 2015 Authors. This is an open access article published by Portland Press Limited and distributed under the Creative Commons Attribution License 3.0. abstract: The 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 down-regulate 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 (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 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. date: 2015-07-28 date_type: published official_url: http://dx.doi.org/10.1042/BJ20150336 oa_status: green full_text_type: pub language: eng primo: open primo_central: open_green article_type_text: Article verified: verified_manual elements_id: 1046184 doi: 10.1042/BJ20150336 lyricists_name: Bowers, Kate lyricists_name: Bowers, Katherine lyricists_id: KBOWE16 lyricists_id: KEBOW26 actors_name: Bowers, Katherine actors_name: McLaren, Erica actors_id: KEBOW26 actors_id: EMCLA53 actors_role: owner actors_role: impersonator full_text_status: public publication: Biochemical Journal volume: 471 number: 1 pagerange: 79-88 issn: 1470-8728 citation: Parkinson, MDJ; Piper, SC; Bright, NA; Evans, JL; Boname, JM; Bowers, K; Lehner, PJ; Parkinson, MDJ; Piper, SC; Bright, NA; Evans, JL; Boname, JM; Bowers, K; Lehner, PJ; Luzio, JP; - view fewer <#> (2015) A non-canonical ESCRT pathway, including His domain phosphotyrosine phosphatase (HD-PTP), is used for down-regulation of virally ubiquitinated MHC Class I. Biochemical Journal , 471 (1) pp. 79-88. 10.1042/BJ20150336 <https://doi.org/10.1042/BJ20150336>. Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/1470409/7/79.full.pdf