Sialylation of MUC4β N-glycans by ST6GAL1 orchestrates human airway epithelial cell differentiation associated with type-2 inflammation

  • JCI Insight. 2019 Mar 7;4(5):e122475. doi: 10.1172/jci.insight.122475.
Xiuxia Zhou  1  2 ,  Carol L Kinlough  3 ,  Rebecca P Hughey  3 ,  Mingzhu Jin  1 ,  Hideki Inoue  1  4 ,  Emily Etling  1 ,  Brian D Modena  1  5 ,  Naftali Kaminski  6 ,  Eugene R Bleecker  7 ,  Deborah A Meyers  7 ,  Nizar N Jarjour  8 ,  John B Trudeau  1  2 ,  Fernando Holguin  9 ,  Anuradha Ray  1  10 ,  Sally E Wenzel  1  2
Affiliations
  • 1. Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh Asthma Institute at University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
  • 2. Department of Environmental & Occupational Health, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, USA.
  • 3. Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
  • 4. Division of Pulmonary and Allergy Medicine, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.
  • 5. Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California, USA.
  • 6. Section of Pulmonary, Critical Care and Sleep Medicine, Yale School of Medicine, New Haven, Connecticut, USA.
  • 7. Department of Medicine, University of Arizona, Tucson, Arizona, USA.
  • 8. Division of Allergy, Pulmonary, and Critical Care Medicine, University of Wisconsin, Madison, Wisconsin, USA.
  • 9. Division of Pulmonary and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, Colorado, USA.
  • 10. Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
PMID: 30730306 DOI: 10.1172/jci.insight.122475
Abstract

Although type-2-induced (T2-induced) epithelial dysfunction is likely to profoundly alter epithelial differentiation and repair in asthma, the mechanisms for these effects are poorly understood. A role for specific mucins, heavily N-glycosylated epithelial glycoproteins, in orchestrating epithelial cell fate in response to T2 stimuli has not previously been investigated. Levels of a sialylated MUC4β isoform were found to be increased in airway specimens from asthmatic patients in association with T2 inflammation. We hypothesized that IL-13 would increase sialylation of MUC4β, thereby altering its function and that the β-galactoside α-2,6-sialyltransferase 1 (ST6GAL1) would regulate the sialylation. Using human biologic specimens and cultured primary human airway epithelial cells (HAECs),we demonstrated that IL-13 increases ST6GAL1-mediated sialylation of MUC4β and that both were increased in asthma, particularly in sputum supernatant and/or fresh isolated HAECs with elevated T2 biomarkers. ST6GAL1-induced sialylation of MUC4β altered its lectin binding and secretion. Both ST6GAL1 and MUC4β inhibited epithelial cell proliferation while promoting goblet cell differentiation. These in vivo and in vitro data provide strong evidence for a critical role for ST6GAL1-induced sialylation of MUC4β in epithelial dysfunction associated with T2-high asthma, thereby identifying specific sialylation pathways as potential targets in asthma.

Keywords
Asthma; Inflammation; Pulmonology; Th2 response.