Chambers Joseph E, Zubkov Nikita, Kubánková Markéta, Nixon-Abell Jonathon, Mela Ioanna, Abreu Susana, Schwiening Max, Lavarda Giulia, López-Duarte Ismael, Dickens Jennifer A, Torres Tomás, Kaminski Clemens F, Holt Liam J, Avezov Edward, Huntington James A, George-Hyslop Peter St, Kuimova Marina K, Marciniak Stefan J
Cambridge Institute for Medical Research (CIMR), Department of Medicine, University of Cambridge, The Keith Peters Building, Hills Road, Cambridge CB2 0XY, UK.
Department of Chemistry, Imperial College London, Wood Lane, London W12 0BZ, UK.
Sci Adv. 2022 Apr 8;8(14):eabm2094. doi: 10.1126/sciadv.abm2094.
Misfolding of secretory proteins in the endoplasmic reticulum (ER) features in many human diseases. In α-antitrypsin deficiency, the pathogenic Z variant aberrantly assembles into polymers in the hepatocyte ER, leading to cirrhosis. We show that α-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-antitrypsin phase transition is promoted during ER stress by an ATF6-mediated unfolded protein response. Furthermore, the ER chaperone calreticulin promotes Z-α-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-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.
内质网（ER）中分泌蛋白的错误折叠是许多人类疾病的特征。在α-抗胰蛋白酶缺乏症中，致病性Z变体在肝细胞内质网中异常聚合成聚合物，导致肝硬化。我们发现α-抗胰蛋白酶聚合物经历液-固相变，形成一种蛋白质基质，通过大小依赖性分子过滤阻碍内质网蛋白的移动。在内质网应激期间，ATF6介导的未折叠蛋白反应促进Z-α-抗胰蛋白酶相变。此外，内质网伴侣钙网蛋白促进Z-α-抗胰蛋白酶固化并增加蛋白质基质硬度。单粒子追踪显示，固化在具有正常内质网形态的细胞中开始，以前认为这些细胞代表健康群体。我们发现，Z-α-抗胰蛋白酶诱导的对内质网应激的超敏反应可以通过内质网伴侣在聚合物基质中的固定来解释。这种以前未被识别的内质网功能障碍机制为理解一组相关的蛋白质病提供了一个模板，并将内质网伴侣确定为潜在的治疗靶点。
