Show simple item record

dc.contributor.authorMenzies, Sam A
dc.contributor.authorVolkmar, Norbert
dc.contributor.authorvan den Boomen, Dick Jh
dc.contributor.authorTimms, Richard T
dc.contributor.authorDickson, Anna S
dc.contributor.authorNathan, James A
dc.contributor.authorLehner, Paul J
dc.date.accessioned2019-01-03T00:30:13Z
dc.date.available2019-01-03T00:30:13Z
dc.date.issued2018-12-13
dc.identifier.issn2050-084X
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/287482
dc.description.abstractMammalian HMG-CoA reductase (HMGCR), the rate-limiting enzyme of the cholesterol biosynthetic pathway and the therapeutic target of statins, is post-transcriptionally regulated by sterol-accelerated degradation. Under cholesterol-replete conditions, HMGCR is ubiquitinated and degraded, but the identity of the E3 ubiquitin ligase(s) responsible for mammalian HMGCR turnover remains controversial. Using systematic, unbiased CRISPR/Cas9 genome-wide screens with a sterol-sensitive endogenous HMGCR reporter, we comprehensively map the E3 ligase landscape required for sterol-accelerated HMGCR degradation. We find that RNF145 and gp78 independently co-ordinate HMGCR ubiquitination and degradation. RNF145, a sterol-responsive ER-resident E3 ligase, is unstable but accumulates following sterol depletion. Sterol addition triggers RNF145 recruitment to HMGCR via Insigs, promoting HMGCR ubiquitination and proteasome-mediated degradation. In the absence of both RNF145 and gp78, Hrd1, a third UBE2G2-dependent E3 ligase, partially regulates HMGCR activity. Our findings reveal a critical role for the sterol-responsive RNF145 in HMGCR regulation and elucidate the complexity of sterol-accelerated HMGCR degradation. Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).
dc.format.mediumElectronic
dc.languageeng
dc.publishereLife Sciences Publications, Ltd
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectAnimals
dc.subjectHumans
dc.subjectMice
dc.subjectCholesterol
dc.subjectUbiquitin-Conjugating Enzymes
dc.subjectUbiquitin-Protein Ligases
dc.subjectHydroxymethylglutaryl CoA Reductases
dc.subjectMembrane Proteins
dc.subjectUbiquitination
dc.subjectReceptors, Autocrine Motility Factor
dc.subjectProteolysis
dc.subjectCRISPR-Cas Systems
dc.titleThe sterol-responsive RNF145 E3 ubiquitin ligase mediates the degradation of HMG-CoA reductase together with gp78 and Hrd1.
dc.typeArticle
prism.publicationDate2018
prism.publicationNameElife
prism.volume7
dc.identifier.doi10.17863/CAM.34788
dcterms.dateAccepted2018-11-19
rioxxterms.versionofrecord10.7554/eLife.40009
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2018-12-13
dc.contributor.orcidVolkmar, Norbert [0000-0003-0766-5606]
dc.contributor.orcidNathan, James A [0000-0002-0248-1632]
dc.contributor.orcidLehner, Paul J [0000-0001-9383-1054]
dc.identifier.eissn2050-084X
rioxxterms.typeJournal Article/Review
pubs.funder-project-idWellcome Trust (210688/Z/18/Z)
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 (201387/Z/16/Z)
pubs.funder-project-idLister Institute of Preventive Medicine (unknown)
pubs.funder-project-idWellcome Trust (100140/Z/12/Z)
cam.issuedOnline2018-12-13


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record

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