{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T00:46:22Z","timestamp":1791852382230,"version":"4.3.4"},"reference-count":81,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"14","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2022,4,8]]},"abstract":"<jats:p>\n                    Misfolding of secretory proteins in the endoplasmic reticulum (ER) features in many human diseases. In \u03b1\n                    <jats:sub>1<\/jats:sub>\n                    -antitrypsin deficiency, the pathogenic Z variant aberrantly assembles into polymers in the hepatocyte ER, leading to cirrhosis. We show that \u03b1\n                    <jats:sub>1<\/jats:sub>\n                    -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-\u03b1\n                    <jats:sub>1<\/jats:sub>\n                    -antitrypsin phase transition is promoted during ER stress by an ATF6-mediated unfolded protein response. Furthermore, the ER chaperone calreticulin promotes Z-\u03b1\n                    <jats:sub>1<\/jats:sub>\n                    -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-\u03b1\n                    <jats:sub>1<\/jats:sub>\n                    -antitrypsin\u2013induced 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.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.abm2094","type":"journal-article","created":{"date-parts":[[2022,4,8]],"date-time":"2022-04-08T13:56:11Z","timestamp":1649426171000},"source":"Crossref","is-referenced-by-count":49,"title":["Z-\u03b1\n                    <sub>1<\/sub>\n                    -antitrypsin polymers impose molecular filtration in the endoplasmic reticulum after undergoing phase transition to a solid state"],"prefix":"10.1126","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4675-0053","authenticated-orcid":true,"given":"Joseph E.","family":"Chambers","sequence":"first","affiliation":[{"name":"Cambridge Institute for Medical Research (CIMR), Department of Medicine, University of Cambridge, The Keith Peters Building, Hills Road, Cambridge CB2 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Research in Chemical Sciences (IAdChem), Universidad Aut\u00f3noma de Madrid, Madrid 28049, Spain."},{"name":"IMDEA Nanociencia, Campus de Cantoblanco, Madrid 28049, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5194-0962","authenticated-orcid":true,"given":"Clemens F.","family":"Kaminski","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering and Biotechnology, University of Cambridge, Philippa Fawcett Drive, Cambridge CB3 0AS, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4002-0861","authenticated-orcid":true,"given":"Liam J.","family":"Holt","sequence":"additional","affiliation":[{"name":"Institute for Systems Genetics, New York University Grossman School of Medicine, 435 E 30th St, New York, NY 10016, 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