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Retarded PDI diffusion and a reductive shift in poise of the calcium depleted endoplasmic reticulum

2015-01Journal article Open access
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dc.contributor.authorAvezov, Edward
dc.contributor.authorKonno, Tasuku
dc.contributor.authorZyryanova, Alisa
dc.contributor.authorChen, Weiyue
dc.contributor.authorLaine, Romain
dc.contributor.authorCrespillo-Casado, Ana
dc.contributor.authorMelo, Eduardo
dc.contributor.authorUshioda, Ryo
dc.contributor.authorNagata, Kazuhiro
dc.contributor.authorKaminski, Clemens F.
dc.contributor.authorHarding, Heather P.
dc.contributor.authorRon, David
dc.date.accessioned2018-12-07T14:53:07Z
dc.date.available2018-12-07T14:53:07Z
dc.date.issued2015-01
dc.description.abstractBackground: Endoplasmic reticulum (ER) lumenal protein thiol redox balance resists dramatic variation in unfolded protein load imposed by diverse physiological challenges including compromise in the key upstream oxidases. Lumenal calcium depletion, incurred during normal cell signaling, stands out as a notable exception to this resilience, promoting a rapid and reversible shift towards a more reducing poise. Calcium depletion induced ER redox alterations are relevant to physiological conditions associated with calcium signaling, such as the response of pancreatic cells to secretagogues and neuronal activity. The core components of the ER redox machinery are well characterized; however, the molecular basis for the calcium-depletion induced shift in redox balance is presently obscure. Results: In vitro, the core machinery for generating disulfides, consisting of ERO1 and the oxidizing protein disulfide isomerase, PDI1A, was indifferent to variation in calcium concentration within the physiological range. However, ER calcium depletion in vivo led to a selective 2.5-fold decline in PDI1A mobility, whereas the mobility of the reducing PDI family member, ERdj5 was unaffected. In vivo, fluorescence resonance energy transfer measurements revealed that declining PDI1A mobility correlated with formation of a complex with the abundant ER chaperone calreticulin, whose mobility was also inhibited by calcium depletion and the calcium depletion-mediated reductive shift was attenuated in cells lacking calreticulin. Measurements with purified proteins confirmed that the PDI1A-calreticulin complex dissociated as Ca2+ concentrations approached those normally found in the ER lumen ([Ca2+] K-0.5max = 190 mu M). Conclusions: Our findings suggest that selective sequestration of PDI1A in a calcium depletion-mediated complex with the abundant chaperone calreticulin attenuates the effective concentration of this major lumenal thiol oxidant, providing a plausible and simple mechanism for the observed shift in ER lumenal redox poise upon physiological calcium depletion.
dc.description.sponsorshipWellcome Trust [Wellcome 084812/Z/08/Z]; European Commission (EU FP7 Beta-Bat) [277713]; Fundacao para a Ciencia e Tecnologia, Portugal [PTDC/QUI-BIQ/119677/2010]
dc.description.versioninfo:eu-repo/semantics/publishedVersion
dc.identifier.doi10.1186/s12915-014-0112-2
dc.identifier.issn1741-7007
dc.identifier.urihttp://hdl.handle.net/10400.1/11358
dc.language.isoeng
dc.peerreviewedyes
dc.publisherBMC
dc.relationDevelopment of novel treatment strategies based on knowledge of cellular dysfunction in diabetes
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectProtein-disulfide-isomerase
dc.subjectRedox
dc.subjectEr
dc.subjectErdj5
dc.subjectInhibitor
dc.subjectOxidation
dc.subjectRelease
dc.subjectSensor
dc.titleRetarded PDI diffusion and a reductive shift in poise of the calcium depleted endoplasmic reticulum
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/FCT/3599-PPCDT/PTDC%2FQUI-BIQ%2F119677%2F2010/PT
oaire.awardURIinfo:eu-repo/grantAgreement/EC/FP7/277713/EU
oaire.citation.startPage2
oaire.citation.titleBMC Biology
oaire.citation.volume13
oaire.fundingStream3599-PPCDT
oaire.fundingStreamFP7
person.familyNamePinho Melo
person.givenNameEduardo
person.identifier1443188
person.identifier.ciencia-id3C1C-C10C-1510
person.identifier.orcid0000-0002-0974-8977
person.identifier.scopus-author-id35566177900
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100008530
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameEuropean Commission
rcaap.rightsopenAccess
rcaap.typearticle
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relation.isAuthorOfPublication.latestForDiscovery5fa1895f-5577-4652-961a-886ec9bf41b1
relation.isProjectOfPublication355a8acc-162a-4ab9-8628-cb6abfec6e02
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