Z-α₁-antitrypsin polymers impose molecular filtration in the endoplasmic reticulum after undergoing phase transition to a solid state
Author(s)
Type
Journal Article
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.
Date Issued
2022-04
Date Acceptance
2022-02-16
Citation
Science Advances, 2022, 8 (14)
ISSN
2375-2548
Publisher
American Association for the Advancement of Science
Journal / Book Title
Science Advances
Volume
8
Issue
14
Copyright Statement
Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).
https://creativecommons.org/licenses/by/4.0/
This is an open-access article distributed under the terms of the Creative Commons Attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
https://creativecommons.org/licenses/by/4.0/
This is an open-access article distributed under the terms of the Creative Commons Attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
License URL
Identifier
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000800335500010&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=a2bf6146997ec60c407a63945d4e92bb
Subjects
ACCUMULATION
ALPHA-1-ANTITRYPSIN
CALRETICULIN
CHAPERONE
FLUORESCENCE CORRELATION SPECTROSCOPY
HUMAN ALPHA(1)-ANTITRYPSIN
LIQUID DROPLETS
Multidisciplinary Sciences
MUTATIONAL ANALYSIS
PEPTIDE-BINDING-SPECIFICITY
PROTEIN
Science & Technology
Science & Technology - Other Topics
Publication Status
Published
Article Number
eabm2094
Date Publish Online
2022-04-08