Z-α₁-antitrypsin polymers impose molecular filtration in the endoplasmic reticulum after undergoing phase transition to a solid state.

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, previ

SUBMITTER: Chambers JE 

PROVIDER: S-EPMC8993113 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature