Z-α 1 -antitrypsin polymers impose molecular filtration in the endoplasmic reticulum after undergoing phase transition to a solid state

• DOI: 10.1126/sciadv.abm2094
• Publication Date: 2022-04-08T17:56:11Z
• Authors: 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-H...; Marina K. Kuimova; Stefan J. Marciniak
• Keywords: Misfolding; Pathogenics; Antitrypsin; Hepatocytes; 2.1 Biological and endogenous factors; Química; Biomedicine and Life Sciences; Endoplasmic Reticulum; 3101 Biochemistry and Cell Biology; Protein Matrix; 31 Biological Sciences; 3. Good health

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.