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

Autor:	Chambers JE; Cambridge Institute for Medical Research (CIMR), Department of Medicine, University of Cambridge, The Keith Peters Building, Hills Road, Cambridge CB2 0XY, UK., Zubkov N; Cambridge Institute for Medical Research (CIMR), Department of Medicine, University of Cambridge, The Keith Peters Building, Hills Road, Cambridge CB2 0XY, UK., Kubánková M; Department of Chemistry, Imperial College London, Wood Lane, London W12 0BZ, UK., Nixon-Abell J; Cambridge Institute for Medical Research (CIMR), Department of Medicine, University of Cambridge, The Keith Peters Building, Hills Road, Cambridge CB2 0XY, UK., Mela I; Department of Chemical Engineering and Biotechnology, University of Cambridge, Philippa Fawcett Drive, Cambridge CB3 0AS, UK., Abreu S; Cambridge Institute for Medical Research (CIMR), Department of Medicine, University of Cambridge, The Keith Peters Building, Hills Road, Cambridge CB2 0XY, UK., Schwiening M; Cambridge Institute for Medical Research (CIMR), Department of Medicine, University of Cambridge, The Keith Peters Building, Hills Road, Cambridge CB2 0XY, UK., Lavarda G; Departamento de Química Orgánica and Institute for Advanced Research in Chemical Sciences (IAdChem), Universidad Autónoma de Madrid, Madrid 28049, Spain., López-Duarte I; Departamento de Química Orgánica and Institute for Advanced Research in Chemical Sciences (IAdChem), Universidad Autónoma de Madrid, Madrid 28049, Spain., Dickens JA; Cambridge Institute for Medical Research (CIMR), Department of Medicine, University of Cambridge, The Keith Peters Building, Hills Road, Cambridge CB2 0XY, UK., Torres T; Departamento de Química Orgánica and Institute for Advanced Research in Chemical Sciences (IAdChem), Universidad Autónoma de Madrid, Madrid 28049, Spain.; IMDEA Nanociencia, Campus de Cantoblanco, Madrid 28049, Spain., Kaminski CF; Department of Chemical Engineering and Biotechnology, University of Cambridge, Philippa Fawcett Drive, Cambridge CB3 0AS, UK., Holt LJ; Institute for Systems Genetics, New York University Grossman School of Medicine, 435 E 30th St, New York, NY 10016, USA., Avezov E; Department of Clinical Neurosciences and UK Dementia Research Institute, University of Cambridge, Cambridge CB2 0AH, UK., Huntington JA; Cambridge Institute for Medical Research (CIMR), Department of Medicine, University of Cambridge, The Keith Peters Building, Hills Road, Cambridge CB2 0XY, UK., George-Hyslop PS; Cambridge Institute for Medical Research (CIMR), Department of Medicine, University of Cambridge, The Keith Peters Building, Hills Road, Cambridge CB2 0XY, UK.; Department of Medicine (Neurology), Temerty Faculty of Medicine, University of Toronto, University Health Network, Toronto, ON M5T 0S8, Canada.; Taub Institute For Research on Alzheimer's Disease and the Ageing Brain, Department of Neurology, Columbia University Irvine Medical Center, 630 West 1/68 Street, New York, NY 10032, USA., Kuimova MK; Department of Chemistry, Imperial College London, Wood Lane, London W12 0BZ, UK., Marciniak SJ; Cambridge Institute for Medical Research (CIMR), Department of Medicine, University of Cambridge, The Keith Peters Building, Hills Road, Cambridge CB2 0XY, UK.; Royal Papworth Hospital, Cambridge CB2 0AY, UK.
Jazyk:	angličtina
Zdroj:	Science advances [Sci Adv] 2022 Apr 08; Vol. 8 (14), pp. eabm2094. Date of Electronic Publication: 2022 Apr 08.
DOI:	10.1126/sciadv.abm2094
Abstrakt:	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.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu