Z-α1-antitrypsin polymers impose molecular filtration in the endoplasmic reticulum after undergoing phase transition to a solid state.
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Authors
Dickens, Jennifer
Publication Date
2022-04-08Journal Title
Sci Adv
ISSN
2375-2548
Publisher
American Association for the Advancement of Science
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Chambers, J., Zubkov, N., Kubánková, M., Nixon-Abell, J., Mela, I., Abreu, S., Schwiening, M., et al. (2022). Z-α1-antitrypsin polymers impose molecular filtration in the endoplasmic reticulum after undergoing phase transition to a solid state.. Sci Adv https://doi.org/10.1126/sciadv.abm2094
Abstract
Misfolding 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.
Sponsorship
Alpha-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
Funder references
Alpha One Foundation (unknown)
Engineering and Physical Sciences Research Council (EP/H018301/1)
Wellcome Trust (093026/Z/10/Z)
Wellcome Trust (089703/Z/09/Z)
Wellcome Trust (100140/Z/12/Z)
Medical Research Council (MR/K015850/1)
Medical Research Council (MR/K02292X/1)
Engineering and Physical Sciences Research Council (EP/L015889/1)
Medical Research Council (MR/R009120/1)
MRC (MR/V028669/1)
Identifiers
External DOI: https://doi.org/10.1126/sciadv.abm2094
This record's URL: https://www.repository.cam.ac.uk/handle/1810/335987
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