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Intact protein folding in the glutathione-depleted endoplasmic reticulum implicates alternative protein thiol reductants

2014-07Journal article Open access
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dc.contributor.authorTsunoda, Satoshi
dc.contributor.authorAvezov, Edward
dc.contributor.authorZyryanova, Alisa
dc.contributor.authorKonno, Tasuku
dc.contributor.authorLeonardo Mendes-Silva
dc.contributor.authorMelo, Eduardo
dc.contributor.authorHarding, Heather P.
dc.contributor.authorRon, David
dc.date.accessioned2018-12-07T14:53:19Z
dc.date.available2018-12-07T14:53:19Z
dc.date.issued2014-07
dc.description.abstractProtein folding homeostasis in the endoplasmic reticulum (ER) requires efficient protein thiol oxidation, but also relies on a parallel reductive process to edit disulfides during the maturation or degradation of secreted proteins. To critically examine the widely held assumption that reduced ER glutathione fuels disulfide reduction, we expressed a modified form of a cytosolic glutathione-degrading enzyme, ChaC1, in the ER lumen. ChaC1(CtoS) purged the ER of glutathione eliciting the expected kinetic defect in oxidation of an ER-localized glutathione-coupled Grx1-roGFP2 optical probe, but had no effect on the disulfide editing-dependent maturation of the LDL receptor or the reduction-dependent degradation of misfolded alpha-1 antitrypsin. Furthermore, glutathione depletion had no measurable effect on induction of the unfolded protein response (UPR); a sensitive measure of ER protein folding homeostasis. These findings challenge the importance of reduced ER glutathione and suggest the existence of alternative electron donor(s) that maintain the reductive capacity of the ER.
dc.description.sponsorshipWellcome Trust [084812/Z/08/Z, 100140]; European Commission EU [277713]; Fundacao para a Ciencia e a Tecnologia [PTDC/QUI-BIQ/119677/2010]
dc.description.versioninfo:eu-repo/semantics/publishedVersion
dc.identifier.doi10.7554/eLife.03421
dc.identifier.issn2050-084X
dc.identifier.urihttp://hdl.handle.net/10400.1/11452
dc.language.isoeng
dc.peerreviewedyes
dc.publisherElife Sciences Publications Ltd
dc.relationDevelopment of novel treatment strategies based on knowledge of cellular dysfunction in diabetes
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectDisulfide-bond formation
dc.subjectLocalized peroxiredoxin
dc.subjectOxidized glutathione
dc.subjectReducing pathways
dc.subjectRedox
dc.subjectIsomerase
dc.subjectEr
dc.subjectCatalysis
dc.subjectOxidation
dc.subjectErdj5
dc.titleIntact protein folding in the glutathione-depleted endoplasmic reticulum implicates alternative protein thiol reductants
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleDevelopment of novel treatment strategies based on knowledge of cellular dysfunction in diabetes
oaire.awardURIinfo:eu-repo/grantAgreement/EC/FP7/277713/EU
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FQUI-BIQ%2F119677%2F2010/PT
oaire.citation.startPagee03421
oaire.citation.titleeLife
oaire.citation.volume3
oaire.fundingStreamFP7
oaire.fundingStream3599-PPCDT
person.familyNameMendes e Silva
person.familyNamePinho Melo
person.givenNameLeonardo
person.givenNameEduardo
person.identifier1443188
person.identifier.ciencia-id7918-CF94-9CF4
person.identifier.ciencia-id3C1C-C10C-1510
person.identifier.orcid0000-0002-5989-637X
person.identifier.orcid0000-0002-0974-8977
person.identifier.ridK-8962-2018
person.identifier.scopus-author-id57201364200
person.identifier.scopus-author-id35566177900
project.funder.identifierhttp://doi.org/10.13039/501100008530
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameEuropean Commission
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccess
rcaap.typearticle
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relation.isAuthorOfPublication5fa1895f-5577-4652-961a-886ec9bf41b1
relation.isAuthorOfPublication.latestForDiscovery155c8f72-bc3a-49da-8bbd-5480d8d312fa
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