Sialylation of MUC4β N-glycans by ST6GAL1 orchestrates human airway epithelial cell differentiation associated with type-2 inflammation
Kinlough, Carol L
Hughey, Rebecca P
Modena, Brian D
Bleecker, Eugene R
Meyers, Deborah A
Jarjour, Nizar N
Trudeau, John B
Wenzel, Sally E
AffiliationUniv Arizona, Dept Med
MetadataShow full item record
PublisherAMER SOC CLINICAL INVESTIGATION INC
CitationZhou, X., Kinlough, C. L., Hughey, R. P., Jin, M., Inoue, H., Etling, E., ... & Jarjour, N. N. (2019). Sialylation of MUC4β N-glycans by ST6GAL1 orchestrates human airway epithelial cell differentiation associated with type-2 inflammation. JCI insight, 4(5).
RightsCopyright © 2019, American Society for Clinical Investigation.
Collection InformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at email@example.com.
AbstractAlthough 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 MUC4 beta 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 MUC4 beta, thereby altering its function and that the beta-galactoside alpha-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 MUC4 beta and that both were increased in asthma, particularly in sputum supernatant and/or fresh isolated HAECs with elevated T2 biomarkers. ST6GAL1-induced sialylation of MUC4 beta altered its lectin binding and secretion. Both ST6GAL1 and MUC4 beta 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 MUC4 beta in epithelial dysfunction associated with T2-high asthma, thereby identifying specific sialylation pathways as potential targets in asthma.
VersionFinal published version
SponsorsNIH [R01 HL069174]; National Heart, Lung, and Blood Institute [R01 HL064937, R01 HL069116, P01 HL103453, R01 HL69167, U01 HL109086, U10 HL109152, R21 AI122071]; National Institute of Allergy and Infectious Diseases [P01 AI106684]; Nikon A1 [NIH 1S10OD019973-01]