{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T09:11:46Z","timestamp":1790759506241,"version":"4.1.0"},"reference-count":56,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,7,5]],"date-time":"2021-07-05T00:00:00Z","timestamp":1625443200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100005640","name":"Flight Attendant Medical Research Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005640","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000897","name":"Cystic Fibrosis Foundation","doi-asserted-by":"publisher","award":["CFF P30 DK072482"],"award-info":[{"award-number":["CFF P30 DK072482"]}],"id":[{"id":"10.13039\/100000897","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R00HL131866 , R01HL152246, R01HL148215, R35HL135710"],"award-info":[{"award-number":["R00HL131866 , R01HL152246, R01HL148215, R35HL135710"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["R03AG059994"],"award-info":[{"award-number":["R03AG059994"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Chronic obstructive pulmonary disease (COPD) is a systemic disease strongly associated with cigarette smoking, airway inflammation, and acute disease exacerbations. Changes in terminal sialylation and fucosylation of asparagine (N)-linked glycans have been documented in COPD, but the role that glycosyltransferases may play in the regulation of N-linked glycans in COPD has not been fully elucidated. Recent studies suggest that modulation of ST6GAL1 (ST6 beta-galactoside alpha-2,6-sialyltransferase-1), which catalyzes terminal \u03b12-6 sialylation of cellular proteins, may regulate inflammation and contribute to COPD phenotype(s). Interestingly, it has been previously demonstrated that ST6GAL1, a Golgi resident protein, can be proteolytically processed by BACE1 (beta-site amyloid precursor protein cleaving enzyme-1) to a circulating form that retains activity. In this study, we showed that loss of ST6GAL1 expression increased interleukin (IL)-6 expression and secretion in human bronchial epithelial cells (HBECs). Furthermore, exposure to cigarette smoke medium\/extract (CSE) or BACE1 inhibition resulted in decreased ST6GAL1 secretion, reduced \u03b12-6 sialylation, and increased IL-6 production in HBECs. Analysis of plasma ST6GAL1 levels in a small COPD patient cohort demonstrated an inverse association with prospective acute exacerbations of COPD (AECOPD), while IL-6 was positively associated. Altogether, these results suggest that reduced ST6GAL1 and \u03b12-6 sialylation augments IL-6 expression\/secretion in HBECs and is associated with poor clinical outcomes in COPD.<\/jats:p>","DOI":"10.3389\/fimmu.2021.693149","type":"journal-article","created":{"date-parts":[[2021,7,5]],"date-time":"2021-07-05T07:16:51Z","timestamp":1625469411000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":28,"title":["ST6GAL1 and \u03b12-6 Sialylation Regulates IL-6 Expression and Secretion in Chronic Obstructive Pulmonary Disease"],"prefix":"10.3389","volume":"12","author":[{"given":"Stefanie","family":"Krick","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E. Scott","family":"Helton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Molly","family":"Easter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seth","family":"Bollenbecker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Denson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rennan","family":"Zaharias","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phillip","family":"Cochran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shia","family":"Vang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elex","family":"Harris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James M.","family":"Wells","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jarrod W.","family":"Barnes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,7,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1093\/glycob\/3.2.97","article-title":"Biological Roles of Oligosaccharides: All of the Theories Are Correct","volume":"3","author":"Varki","year":"1993","journal-title":"Glycobiology"},{"key":"B2","article-title":"Essential","volume-title":"Glycobiology. Cold Spring Harbor","author":"Varki","year":"2009"},{"key":"B3","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1093\/glycob\/cww086","article-title":"Biological Roles of Glycans","volume":"27","author":"Varki","year":"2017","journal-title":"Glycobiology"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-07-1340","article-title":"Alpha 2-6-Linked Sialic Acids on N-Glycans Modulate Carcinoma Differentiation In Vivo","volume":"68","author":"Hedlund","year":"2008","journal-title":"Cancer Res"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.11699","article-title":"ST6Gal-I Overexpression Facilitates Prostate Cancer Progression via the PI3K\/Akt\/GSK-3beta\/Beta-Catenin Signaling Pathway","volume":"7","author":"Wei","year":"2016","journal-title":"Oncotarget"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.13845","article-title":"Elevation of Beta-Galactoside Alpha2,6-Sialyltransferase 1 in a Fructoseresponsive Manner Promotes Pancreatic Cancer Metastasis","volume":"8","author":"Hsieh","year":"2017","journal-title":"Oncotarget"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.593392","article-title":"Beta-Galactoside Alpha2,6-Sialyltranferase 1 Promotes Transforming Growth Factor-Beta-Mediated Epithelial-Mesenchymal Transition","volume":"289","author":"Lu","year":"2014","journal-title":"J Biol Chem"},{"key":"B8","doi-asserted-by":"publisher","first-page":"898","DOI":"10.1093\/glycob\/cwy065","article-title":"Prognostic Role of the Sialyltransferase ST6GAL1 in Ovarian Cancer","volume":"28","author":"Wichert","year":"2018","journal-title":"Glycobiology"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3892\/ol.2019.10458","article-title":"ST6GAL1: A Key Player in Cancer (Review)","volume":"18","author":"Garnham","year":"2019","journal-title":"Oncol Lett"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.31737","article-title":"Modification of Alpha2,6-Sialylation Mediates the Invasiveness and Tumorigenicity of Non-Small Cell Lung Cancer Cells In Vitro and In Vivo via Notch1\/Hes1\/MMPs Pathway","volume":"143","author":"Yuan","year":"2018","journal-title":"Int J Cancer"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M511826200","article-title":"The ST6GalNAc-I Sialyltransferase Localizes Throughout the Golgi and Is Responsible for the Synthesis of the Tumor-Associated Sialyl-Tn O-Glycan in Human Breast Cance","volume":"281","author":"Sewell","year":"2006","journal-title":"J Biol Chem"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-018-0271-7","article-title":"Glycosylation Controls Cooperative PECAM-VEGFR2-\u03b23 Integrin Functions at the Endothelial Surface for Tumor Angiogenesis","volume":"37","author":"Imamaki","year":"2018","journal-title":"Oncogene"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2017.243","article-title":"Contribution of Vascular Endothelial Growth Factor Receptor-2 Sialylation to the Process of Angiogenesis","volume":"36","author":"Chiodelli","year":"2017","journal-title":"Oncogene"},{"key":"B14","doi-asserted-by":"publisher","first-page":"e0241850","DOI":"10.1371\/journal.pone.0241850","article-title":"Regulation of Inflammatory Signaling by the ST6Gal-I Sialyltransferase","volume":"15","author":"Holdbrooks","year":"2020","journal-title":"PloS One"},{"key":"B15","doi-asserted-by":"publisher","first-page":"207","DOI":"10.3390\/cancers10060207","article-title":"Hypersialylation in Cancer: Modulation of Inflammation and Therapeutic Opportunitie","volume":"10","author":"Rodrigues","year":"2018","journal-title":"Cancers (Basel)"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-12-3424","article-title":"ST6Gal-I Protein Expression Is Upregulated in Human Epithelial Tumors and Correlates With Stem Cell Markers in Normal Tissues and Colon Cancer Cell Lines","volume":"73","author":"Swindall","year":"2013","journal-title":"Cancer Res"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.276063","article-title":"ST6Gal-I Regulates Macrophage Apoptosis via \u03b12-6 Sialylation of the TNFR1 Death Receptor","volume":"286","author":"Liu","year":"2011","journal-title":"J Biol Chem"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.066696","article-title":"Decrease of Sialic Acid Residues as an Eat-Me Signal on the Surface of Apoptotic Lymphocytes","volume":"123","author":"Meesmann","year":"2010","journal-title":"J Cell Sci"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA117.001194","article-title":"The ST6Gal-I Sialyltransferase Protects Tumor Cells Against Hypoxia by Enhancing HIF-1\u03b1 Signaling","volume":"293","author":"Jones","year":"2018","journal-title":"J Biol Chem"},{"key":"B20","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1172\/jci.insight.122475","article-title":"Sialylation of MUC4beta N-Glycans by ST6GAL1 Orchestrates Human Airway Epithelial Cell Differentiation Associated With Type-2 Inflammation","volume":"4","author":"Zhou","year":"2019","journal-title":"JCI Insight"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.thorsurg.2013.01.009","article-title":"Tobacco Smoking: The Leading Cause of Preventable Disease Worldwide","volume":"23","author":"Samet","year":"2013","journal-title":"Thorac Surg Clin"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-2600(20)30105-3","article-title":"Prevalence and Attributable Health Burden of Chronic Respiratory Diseases, 1990-2017: A Systematic Analysis for the Global Burden of Disease Study 2017","volume":"8","year":"2020","journal-title":"Lancet Respir Med"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1136\/thx.2005.040527","article-title":"Severe Acute Exacerbations and Mortality in Patients With Chronic Obstructive Pulmonary Disease","volume":"60","author":"Soler-Cataluna","year":"2005","journal-title":"Thorax"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.247981","article-title":"Endothelial Surface N-Glycans Mediate Monocyte Adhesion and are Targets for Anti-Inflammatory Effects of Peroxisome Proliferator-Activated Receptor Gamma Ligands","volume":"286","author":"Chacko","year":"2011","journal-title":"J Biol Chem"},{"key":"B25","doi-asserted-by":"publisher","first-page":"101498","DOI":"10.1016\/j.redox.2020.101498","article-title":"Hydrogen Peroxide Regulates Endothelial Surface N-Glycoforms to Control Inflammatory Monocyte Rolling and Adhesion","volume":"34","author":"McDonald","year":"2020","journal-title":"Redox Biol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.116.309637","article-title":"GlycA Is a Novel Biomarker of Inflammation and Subclinical Cardiovascular Disease in Psoriasi","volume":"119","author":"Joshi","year":"2016","journal-title":"Circ Res"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/s41581-019-0129-4","article-title":"Glycosylation in Health and Disease","volume":"15","author":"Reily","year":"2019","journal-title":"Nat Rev Nephrol"},{"key":"B28","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1186\/s12967-018-1695-0","article-title":"N-Glycosylation Patterns of Plasma Proteins and Immunoglobulin G in Chronic Obstructive Pulmonary Disease","volume":"16","author":"Pavic","year":"2018","journal-title":"J Transl Med"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.cca.2020.03.041","article-title":"Glycoprotein Biomarkers and Analysis in Chronic Obstructive Pulmonary Disease and Lung Cancer With Special Focus on Serum Immunoglobulin G","volume":"506","author":"Komaromy","year":"2020","journal-title":"Clinica Chimica Acta"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1801045","article-title":"Circulating Truncated Alpha-1 Antitrypsin Glycoprotein in Patient Plasma Retains Anti-Inflammatory Capacit","volume":"202","author":"Reeves","year":"2019","journal-title":"J Immunol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1111\/j.1537-2995.2006.01004.x","article-title":"Biochemical, Molecular Characterization, and Glycoproteomic Analyses of Alpha(1)-Proteinase Inhibitor Products Used for Replacement Therapy","volume":"46","author":"Kolarich","year":"2006","journal-title":"Transfusion"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.15326\/jcopdf.6.5.2019.0149","article-title":"COPDGene(\u00ae) 2019: Redefining the Diagnosis of Chronic Obstructive Pulmonary Diseas","volume":"6","author":"Lowe","year":"2019","journal-title":"Chronic Obstr Pulm Dis"},{"key":"B33","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1183\/13993003.00164-2019","article-title":"Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease: The GOLD Science Committee Report 2019","volume":"53","author":"Singh","year":"2019","journal-title":"Eur Respir J"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201908-1590ST","article-title":"Standardization of Spirometry 2019 Update. An Official American Thoracic Society and European Respiratory Society Technical Statemen","volume":"200","author":"Graham","year":"2019","journal-title":"Am J Respir Crit Care Med"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201710-1981ST","article-title":"Laboratories ATSCoPSfPF. Recommendations for a Standardized Pulmonary Function Report. An Official American Thoracic Society Technical Statemen","volume":"196","author":"Culver","year":"2017","journal-title":"Am J Respir Crit Care Med"},{"key":"B36","doi-asserted-by":"publisher","first-page":"46s","DOI":"10.1183\/09031936.03.00078002","article-title":"COPD Exacerbations: Definitions and Classifications","volume":"41","author":"Burge","year":"2003","journal-title":"Eur Respir J Suppl"},{"key":"B37","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fendo.2018.00708","article-title":"FGF23 Induction of O-Linked N-Acetylglucosamine Regulates IL-6 Secretion in Human Bronchial Epithelial Cell","volume":"9","author":"Krick","year":"2018","journal-title":"Front Endocrinol"},{"key":"B38","first-page":"36","article-title":"Image Processing With Image","volume":"11","author":"Abramoff","year":"2004","journal-title":"Biophotonics Int"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2089","article-title":"NIH Image to ImageJ: 25 Years of Image Analysis","volume":"9","author":"Schneider","year":"2012","journal-title":"Nat Methods"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1002\/mrd.22747","article-title":"Cigarette Smoking Alters Sialylation in the Fallopian Tube of Women, With Implications for the Pathogenesis of Ectopic Pregnancy","volume":"83","author":"Nio-Kobayashi","year":"2016","journal-title":"Mol Reprod Dev"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1093\/glycob\/cwp003","article-title":"Molecular Insights Into Beta-Galactoside Alpha2,6-Sialyltransferase Secretion In Vivo","volume":"19","author":"Kitazume","year":"2009","journal-title":"Glycobiology"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.241509198","article-title":"Alzheimer's Beta-Secretase, Beta-Site Amyloid Precursor Protein-Cleaving Enzyme, is Responsible for Cleavage Secretion of a Golgi-Resident Sialyltransferase","volume":"98","author":"Kitazume","year":"2001","journal-title":"Proc Natl Acad Sci USA"},{"key":"B43","doi-asserted-by":"publisher","first-page":"1260419","DOI":"10.1126\/science.1260419","article-title":"Proteomics. Tissue-Based Map of the Human Proteome","volume":"347","author":"Uhlen","year":"2015","journal-title":"Science"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1126\/science.aal3321","article-title":"A Subcellular Map of the Human Proteome","volume":"356","author":"Thul","year":"2017","journal-title":"Science"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1093\/glycob\/cwz096","article-title":"Modulation of Hepatocyte Sialylation Drives Spontaneous Fatty Liver Disease and Inflammation","volume":"30","author":"Oswald","year":"2020","journal-title":"Glycobiology"},{"key":"B46","doi-asserted-by":"publisher","first-page":"40256","DOI":"10.1038\/srep40256","article-title":"TNF-\u03b1 Regulates the Proteolytic Degradation of ST6Gal-1 and Endothelial Cell-Cell Junctions Through Upregulating Expression of BACE1","volume":"7","author":"Deng","year":"2017","journal-title":"Sci Rep"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1126\/science.286.5440.735","article-title":"\u03b2-Secretase Cleavage of Alzheimer's Amyloid Precursor Protein by the Transmembrane Aspartic Protease BACE","volume":"286","author":"Vassar","year":"1999","journal-title":"Science"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.97.4.1456","article-title":"Human Aspartic Protease Memapsin 2 Cleaves the \u03b2-Secretase Site of \u03b2-Amyloid Precursor Protein","volume":"97","author":"Lin","year":"2000","journal-title":"Proc Natl Acad Sci"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1006\/mcne.1999.0811","article-title":"Identification of a Novel Aspartic Protease (Asp 2) as Beta-Secretase","volume":"14","author":"Hussain","year":"1999","journal-title":"Mol Cell Neurosci"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1038\/990114","article-title":"Purification and Cloning of Amyloid Precursor Protein Beta-Secretase From Human Brain","volume":"402","author":"Sinha","year":"1999","journal-title":"Nature"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.104406","article-title":"Role for Hepatic and Circulatory ST6Gal-1 Sialyltransferase in Regulating Myelopoiesis","volume":"285","author":"Jones","year":"2010","journal-title":"J Biol Chem"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M704766200","article-title":"\u03b2-Galactoside \u03b12,6-Sialyltransferase I Cleavage by BACE1 Enhances the Sialylation of Soluble Glycoprotein","volume":"282","author":"Sugimoto","year":"2007","journal-title":"J Biol Chem"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1523968113","article-title":"Cobb BA. B-Cell-Independent Sialylation of Ig","volume":"113","author":"Jones","year":"2016","journal-title":"Proc Natl Acad Sci USA"},{"key":"B54","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fimmu.2018.02150","article-title":"Systemic ST6Gal-1 Is a Pro-Survival Factor for Murine Transitional B Cell","volume":"9","author":"Irons","year":"2018","journal-title":"Front Immunol"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2006-04-014779","article-title":"Altered Granulopoietic Profile and Exaggerated Acute Neutrophilic Inflammation in Mice With Targeted Deficiency in the Sialyltransferase ST6Gal I","volume":"108","author":"Nasirikenari","year":"2006","journal-title":"Blood"},{"key":"B56","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fimmu.2019.00048","article-title":"Recombinant Sialyltransferase Infusion Mitigates Infection-Driven Acute Lung Inflammatio","volume":"10","author":"Nasirikenari","year":"2019","journal-title":"Front Immunol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.693149\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,7,5]],"date-time":"2021-07-05T07:16:56Z","timestamp":1625469416000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.693149\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,5]]},"references-count":56,"alternative-id":["10.3389\/fimmu.2021.693149"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2021.693149","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,5]]},"article-number":"693149"}}