Z-α <sub>1</sub> -antitrypsin polymers impose molecular filtration in the endoplasmic reticulum after undergoing phase transition to a solid state
Joseph E. Chambers, Nikita Zubkov, Markéta Kubánková, Jonathon Nixon‐Abell, Ioanna Mela, Susana Abreu, Max Schwiening, Giulia Lavarda, Ismael López‐Duarte, Jennifer A. Dickens, Tomás Torres⊗, Clemens F. Kaminski, Liam J. Holt, Edward Avezov, James A. Huntington, Peter St George‐Hyslop, Marina K. Kuimova, Stefan J. Marciniak
Abstract
Misfolding of secretory proteins in the endoplasmic reticulum (ER) features in many human diseases. In α 1 -antitrypsin deficiency, the pathogenic Z variant aberrantly assembles into polymers in the hepatocyte ER, leading to cirrhosis. We show that α 1 -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-α 1 -antitrypsin phase transition is promoted during ER stress by an ATF6-mediated unfolded protein response. Furthermore, the ER chaperone calreticulin promotes Z-α 1 -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-α 1 -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.