title: Influenza A induces the major secreted airway mucin MUC5AC in a protease-EGFR-extracellular regulated kinase-Sp1-dependent pathway.
abstract: Mucins, the main glycoproteins present within mucus, modulate the rheologic properties of airways and participate in lung defense. They are thought to be able to trap and eliminate microorganisms from the lung. Among the mucins secreted in the lung, MUC5AC is the most prominent factor secreted by surface epithelial cells. Although much is known about the signaling pathways involved in the regulation of MUC5AC by host factors such as cytokines or proteases, less is known about the pathways triggered by microorganisms and, specifically, by influenza A virus (IAV). We therefore set up experiments to dissect the molecular mechanisms responsible for the potential modulation of MUC5AC by IAV. Using epithelial cells, C57/Bl6 mice, and IAV strains, we measured MUC5AC expression at the RNA and protein levels, specificity protein 1 (Sp1) activation, and protease activity. Intermediate molecular partners were confirmed using pharmacological inhibitors, blocking antibodies, and small interfering (si)RNAs. We showed in vitro and in vivo that IAV up-regulates epithelial cell-derived MUC5AC and Muc5ac expression in mice, both at transcriptional (through the induction of Sp1) and translational levels. In addition, we determined that this induction was dependent on a protease-epithelial growth factor receptor-extracellular regulated kinase-Sp1 signaling cascade, involving in particular the human airway trypsin. Our data point to MUC5AC as a potential modulatory mechanism by which the lung epithelia respond to IAV infection, and we dissect, for the first time to the best of our knowledge, the molecular partners involved. Future experiments using MUC5AC-targeted strategies should help further unravel the pathophysiological consequences of IAV-induced MUC5AC expression for lung homeostasis.
authors.affiliation: Unité Défense Innée et Inflammation, Institut Pasteur, Paris, France.
authors.forename: Diane
authors.initials: D
authors.lastname: Barbier
authors.forename: Ignacio
authors.initials: I
authors.lastname: Garcia-Verdugo
authors.forename: Julien
authors.initials: J
authors.lastname: Pothlichet
authors.forename: Roxana
authors.initials: R
authors.lastname: Khazen
authors.forename: Delphyne
authors.initials: D
authors.lastname: Descamps
authors.forename: Karine
authors.initials: K
authors.lastname: Rousseau
authors.forename: David
authors.initials: D
authors.lastname: Thornton
authors.forename: Mustapha
authors.initials: M
authors.lastname: Si-Tahar
authors.forename: Lhousseine
authors.initials: L
authors.lastname: Touqui
authors.forename: Michel
authors.initials: M
authors.lastname: Chignard
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Sallenave
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism; D000072198:ADAM17 Protein; D000818:Animals; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000378:metabolism / Q000821:virology; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009980:Influenza A virus / Q000378:metabolism*; D007251:Influenza, Human / Q000378:metabolism; D008168:Lung / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D055271:Mucin 5AC / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D010447:Peptide Hydrolases / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D014357:Trypsin / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D014779:Virus Replication / Q000235:genetics
chemical_list: D055271:Mucin 5AC; D016329:Sp1 Transcription Factor; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D010447:Peptide Hydrolases; D014357:Trypsin; D051722:ADAM Proteins; D000072198:ADAM17 Protein