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Reduced Sialylation of Airway Mucin Impairs Mucus Transport by Altering the Biophysical Properties of Mucin.
Harris, Elex S; McIntire, Hannah J; Mazur, Marina; Schulz-Hildebrandt, Hinnerk; Leung, Hui Min; Tearney, Guillermo J; Krick, Stefanie; Rowe, Steven M; Barnes, Jarrod W.
Afiliación
  • Harris ES; Gregory Fleming James Cystic Fibrosis Research Center, Univ. of Alabama at Birmingham, Birmingham, AL, USA.
  • McIntire HJ; Gregory Fleming James Cystic Fibrosis Research Center, Univ. of Alabama at Birmingham, Birmingham, AL, USA.
  • Mazur M; Gregory Fleming James Cystic Fibrosis Research Center, Univ. of Alabama at Birmingham, Birmingham, AL, USA.
  • Schulz-Hildebrandt H; Massachusetts General Hospital, Boston, MA, USA.
  • Leung HM; Massachusetts General Hospital, Boston, MA, USA.
  • Tearney GJ; Massachusetts General Hospital, Boston, MA, USA.
  • Krick S; Gregory Fleming James Cystic Fibrosis Research Center, Univ. of Alabama at Birmingham, Birmingham, AL, USA.
  • Rowe SM; Gregory Fleming James Cystic Fibrosis Research Center, Univ. of Alabama at Birmingham, Birmingham, AL, USA.
  • Barnes JW; Gregory Fleming James Cystic Fibrosis Research Center, Univ. of Alabama at Birmingham, Birmingham, AL, USA.
Res Sq ; 2024 May 31.
Article en En | MEDLINE | ID: mdl-38853971
ABSTRACT
Mucus stasis is a pathologic hallmark of muco-obstructive diseases, including cystic fibrosis (CF). Mucins, the principal component of mucus, are extensively modified with hydroxyl (O)-linked glycans, which are largely terminated by sialic acid. Sialic acid is a negatively charged monosaccharide and contributes to the biochemical/biophysical properties of mucins. Reports suggest that mucin sialylation may be altered in CF; however, the consequences of reduced sialylation on mucus clearance have not been fully determined. Here, we investigated the consequences of reduced sialylation on the charge state and conformation of the most prominent airway mucin, MUC5B, and defined the functional consequences of reduced sialylation on mucociliary transport (MCT). Reduced sialylation contributed to a lower charged MUC5B form and decreased polymer expansion. The inhibition of total mucin sialylation de novo impaired MCT in primary human bronchial epithelial cells and rat airways, and specific α-2,3 sialylation blockade was sufficient to recapitulate these findings. Finally, we show that ST3 beta-galactoside alpha-2,3-sialyltransferase (ST3Gal1) expression is downregulated in CF and partially restored by correcting CFTR via Elexacaftor/Tezacaftor/Ivacaftor treatment. Overall, this study demonstrates the importance of mucin sialylation in mucus clearance and identifies decreased sialylation by ST3Gal1 as a possible therapeutic target in CF and potentially other muco-obstructive diseases.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Res Sq Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
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XML
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Res Sq Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos