{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T10:51:59Z","timestamp":1782989519977,"version":"3.54.5"},"reference-count":56,"publisher":"Portland Press Ltd.","issue":"7","license":[{"start":{"date-parts":[[2022,3,24]],"date-time":"2022-03-24T00:00:00Z","timestamp":1648080000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2022,4,14]]},"abstract":"<jats:p>\u03b11-antitrypsin (AAT) is a serine protease inhibitor synthesized in hepatocytes and protects the lung from damage by neutrophil elastase. AAT gene mutations result in AAT deficiency (AATD), which leads to lung and liver diseases. The AAT Z variant forms polymer within the endoplasmic reticulum (ER) of hepatocytes and results in reduction in AAT secretion and severe disease. Previous studies demonstrated a secretion defect of AAT in LMAN1 deficient cells, and mild decreases in AAT levels in male LMAN1 and MCFD2 deficient mice. LMAN1 is a transmembrane lectin that forms a complex with a small soluble protein MCFD2. The LMAN1\u2013MCFD2 protein complex cycles between the ER and the Golgi. Here, we report that LMAN1 and MCFD2 knockout (KO) HepG2 and HEK293T cells display reduced AAT secretion and elevated intracellular AAT levels due to a delayed ER-to-Golgi transport of AAT. Secretion defects in KO cells were rescued by wild-type LMAN1 or MCFD2, but not by mutant proteins. Elimination of the second glycosylation site of AAT abolished LMAN1 dependent secretion. Co-immunoprecipitation experiment in MCFD2 KO cells suggested that AAT interaction with LMAN1 is independent of MCFD2. Furthermore, our results suggest that secretion of the Z variant, both monomers and polymers, is also LMAN1-dependent. Results provide direct evidence supporting that the LMAN1\u2013MCFD2 complex is a cargo receptor for the ER-to-Golgi transport of AAT and that interactions of LMAN1 with an N-glycan of AAT is critical for this process. These results have implications in production of recombinant AAT and in developing treatments for AATD patients.<\/jats:p>","DOI":"10.1042\/bcj20220055","type":"journal-article","created":{"date-parts":[[2022,3,25]],"date-time":"2022-03-25T00:27:24Z","timestamp":1648168044000},"page":"839-855","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["LMAN1\u2013MCFD2 complex is a cargo receptor for the ER-Golgi transport of \u03b11-antitrypsin"],"prefix":"10.1042","volume":"479","author":[{"given":"Yuan","family":"Zhang","sequence":"first","affiliation":[{"name":"Genomic Medicine Institute, Lerner Research Institute of Cleveland Clinic, Cleveland, OH, U.SA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Pathology, Karamay Central Hospital, Karamay, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunlei","family":"Zheng","sequence":"additional","affiliation":[{"name":"Genomic Medicine Institute, Lerner Research Institute of Cleveland Clinic, Cleveland, OH, U.SA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Wei","sequence":"additional","affiliation":[{"name":"Genomic Medicine Institute, Lerner Research Institute of Cleveland Clinic, Cleveland, OH, U.SA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian T.","family":"Emmer","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Life Sciences Institute, University of Michigan, Ann Arbor, MI, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7786-7580","authenticated-orcid":false,"given":"Bin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Genomic Medicine Institute, Lerner Research Institute of Cleveland Clinic, Cleveland, OH, U.SA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2022,4,11]]},"reference":[{"key":"2022041111065521600_BCJ-2022-0055C1","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1016\/j.molmed.2013.10.007","article-title":"The molecular and cellular pathology of alpha(1)-antitrypsin deficiency","volume":"20","year":"2014","journal-title":"Trends Mol. 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