{"doi":"10.1126/sciadv.abm2094","title":"Z-α <sub>1</sub> -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 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.","journal":"Science Advances","year":2022,"id":240433,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":45,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9541,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":867784,"name":"Nikita Zubkov","orcid":"0000-0001-8912-0073","position":1,"is_corresponding":false},{"id":867785,"name":"Markéta Kubánková","orcid":"0000-0001-7086-8938","position":2,"is_corresponding":false},{"id":626370,"name":"Jonathon Nixon‐Abell","orcid":"0000-0003-4169-0012","position":3,"is_corresponding":false},{"id":628553,"name":"Ioanna Mela","orcid":"0000-0002-2914-9971","position":4,"is_corresponding":false},{"id":867786,"name":"Susana Abreu","orcid":"0000-0002-3146-5762","position":5,"is_corresponding":false},{"id":867787,"name":"Max Schwiening","orcid":"0000-0001-8134-534X","position":6,"is_corresponding":false},{"id":867788,"name":"Giulia Lavarda","orcid":"0000-0003-2171-008X","position":7,"is_corresponding":false},{"id":867789,"name":"Ismael López‐Duarte","orcid":"0000-0002-9941-8305","position":8,"is_corresponding":false},{"id":867790,"name":"Jennifer A. Dickens","orcid":"0000-0001-9977-6586","position":9,"is_corresponding":false},{"id":867791,"name":"Tomás Torres⊗","orcid":"0000-0001-9335-6935","position":10,"is_corresponding":false},{"id":353383,"name":"Clemens F. Kaminski","orcid":"0000-0002-5194-0962","position":11,"is_corresponding":false},{"id":479006,"name":"Liam J. Holt","orcid":"0000-0002-4002-0861","position":12,"is_corresponding":false},{"id":867792,"name":"Edward Avezov","orcid":"0000-0002-2894-0585","position":13,"is_corresponding":false},{"id":411504,"name":"James A. Huntington","orcid":"0000-0003-0076-7204","position":14,"is_corresponding":false},{"id":461714,"name":"Peter St George‐Hyslop","orcid":"0000-0003-0796-7209","position":15,"is_corresponding":false},{"id":867793,"name":"Marina K. Kuimova","orcid":"0000-0003-2383-6014","position":16,"is_corresponding":false},{"id":812150,"name":"Stefan J. Marciniak","orcid":"0000-0001-8472-7183","position":17,"is_corresponding":false},{"id":867783,"name":"Joseph E. Chambers","orcid":"0000-0003-4675-0053","position":0,"is_corresponding":true}],"reference_count":81,"raw_metadata":null,"created_at":"2026-07-19T00:22:46.554789Z","pmid":"35394846","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}