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dc.contributor.authorChambers, Joseph
dc.contributor.authorZubkov, Nikita
dc.contributor.authorKubánková, Markéta
dc.contributor.authorNixon-Abell, Jonathon
dc.contributor.authorMela, Ioanna
dc.contributor.authorAbreu, Susana
dc.contributor.authorSchwiening, Max
dc.contributor.authorLavarda, Giulia
dc.contributor.authorLópez-Duarte, Ismael
dc.contributor.authorDickens, Jennifer
dc.contributor.authorTorres, Tomás
dc.contributor.authorKaminski, Clemens
dc.contributor.authorHolt, Liam J
dc.contributor.authorAvezov, Edward
dc.contributor.authorHuntington, Jim
dc.contributor.authorGeorge-Hyslop, Peter St
dc.contributor.authorKuimova, Marina K
dc.contributor.authorMarciniak, Stefan
dc.date.accessioned2022-04-11T23:30:07Z
dc.date.available2022-04-11T23:30:07Z
dc.date.issued2022-04-08
dc.identifier.issn2375-2548
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/335987
dc.description.abstractMisfolding of secretory proteins in the endoplasmic reticulum (ER) features in many human diseases. In α1-antitrypsin deficiency, the pathogenic Z variant aberrantly assembles into polymers in the hepatocyte ER, leading to cirrhosis. We show that α1-antitrypsin polymers undergo a liquid:solid phase transition, forming a protein matrix that retards mobility of ER proteins by size-dependent molecular filtration. The Z-α1-antitrypsin phase transition is promoted during ER stress by an ATF6-mediated unfolded protein response. Furthermore, the ER chaperone calreticulin promotes Z-α1-antitrypsin solidification and increases protein matrix stiffness. Single-particle tracking reveals that solidification initiates in cells with normal ER morphology, previously assumed to represent a healthy pool. We show that Z-α1-antitrypsin-induced hypersensitivity to ER stress can be explained by immobilization of ER chaperones within the polymer matrix. This previously unidentified mechanism of ER dysfunction provides a template for understanding a diverse group of related proteinopathies and identifies ER chaperones as potential therapeutic targets.
dc.description.sponsorshipAlpha-1 Foundation Grifols Alpha-1-Antitrypsin Laurell’s Training Award National Biofilms Innovation Centre MINECO MedImmune Infinitus NIH The American Cancer Society The Pershing Square Sohn Cancer Research Award The Chan Zuckerberg Initiative UK Dementia Research Institute grant Canadian Institutes of Health Research US Alzheimer Society Integrated Biological Imaging Network
dc.publisherAmerican Association for the Advancement of Science
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.titleZ-α1-antitrypsin polymers impose molecular filtration in the endoplasmic reticulum after undergoing phase transition to a solid state.
dc.typeArticle
dc.publisher.departmentC.I.M.R. Medicine
dc.date.updated2022-02-10T11:51:58Z
prism.publicationNameSci Adv
dc.identifier.doi10.17863/CAM.83419
dcterms.dateAccepted2022-02-09
rioxxterms.versionofrecord10.1126/sciadv.abm2094
rioxxterms.versionVoR
dc.contributor.orcidChambers, Joseph [0000-0003-4675-0053]
dc.contributor.orcidZubkov, Nikita [0000-0001-8912-0073]
dc.contributor.orcidKubánková, Markéta [0000-0001-7086-8938]
dc.contributor.orcidNixon-Abell, Jonathon [0000-0003-4169-0012]
dc.contributor.orcidMela, Ioanna [0000-0002-2914-9971]
dc.contributor.orcidAbreu, Susana [0000-0002-3146-5762]
dc.contributor.orcidSchwiening, Max [0000-0001-8134-534X]
dc.contributor.orcidLavarda, Giulia [0000-0003-2171-008X]
dc.contributor.orcidLópez-Duarte, Ismael [0000-0002-9941-8305]
dc.contributor.orcidTorres, Tomás [0000-0001-9335-6935]
dc.contributor.orcidKaminski, Clemens [0000-0002-5194-0962]
dc.contributor.orcidHolt, Liam J [0000-0002-4002-0861]
dc.contributor.orcidAvezov, Edward [0000-0002-2894-0585]
dc.contributor.orcidHuntington, Jim [0000-0003-0076-7204]
dc.contributor.orcidGeorge-Hyslop, Peter St [0000-0003-0796-7209]
dc.contributor.orcidKuimova, Marina K [0000-0003-2383-6014]
dc.contributor.orcidMarciniak, Stefan [0000-0001-8472-7183]
dc.identifier.eissn2375-2548
rioxxterms.typeJournal Article/Review
pubs.funder-project-idAlpha One Foundation (unknown)
pubs.funder-project-idEngineering and Physical Sciences Research Council (EP/H018301/1)
pubs.funder-project-idWellcome Trust (093026/Z/10/Z)
pubs.funder-project-idWellcome Trust (089703/Z/09/Z)
pubs.funder-project-idWellcome Trust (100140/Z/12/Z)
pubs.funder-project-idMedical Research Council (MR/K015850/1)
pubs.funder-project-idMedical Research Council (MR/K02292X/1)
pubs.funder-project-idEngineering and Physical Sciences Research Council (EP/L015889/1)
pubs.funder-project-idMedical Research Council (MR/R009120/1)
pubs.funder-project-idMRC (MR/V028669/1)
cam.issuedOnline2022-04-08
cam.depositDate2022-02-10
pubs.licence-identifierapollo-deposit-licence-2-1
pubs.licence-display-nameApollo Repository Deposit Licence Agreement


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