Loss of core-fucosylation of SPARC impairs collagen binding and contributes to COPD

Tsai Jung Wu, Sheng Hung Wang, Eric Sheng Wen Chen, Hsiu Hui Tsai, Yi Chieh Chang, Yi Hsin Tseng, John Yu*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

6 Scopus citations

Abstract

Chronic obstructive pulmonary disease (COPD) is a progressive lung disease with high morbidity and mortality worldwide. Although several mechanisms to account for deleterious immune effects were proposed, molecular description for the underlying alveolar structural alterations for COPD is lacking. Here, silencing of α1,6-fucosyltransferase (Fut8), the enzyme for core-fucosylation and highly expressed in lung stem cells, resulted in alveolar structural changes in lung organoids, recapitulating COPD. Site-specific mass spectrometry analysis demonstrated that the secreted protein acidic and rich in cysteine (SPARC), which binds collagen, contains a core-fucosylation site in its VCSNDNcfK glycopeptide. Biacore assay showed markedly reduced collagen binding of SPARC lacking core fucosylation. Molecular dynamics analysis revealed that core fucosylation of SPARC-induced dynamic conformational changes in its N-glycan, allowing terminal galactose and N-acetylglucosamine to interact with K150, P261 and H264 residues, thereby promoting collagen binding. Site-specific mutagenesis of these residues also resulted in low affinity for collagen binding. Moreover, loss of collagen and decline of core fucosylation were observed in COPD lung tissues. These findings provide a new mechanistic insight into the role of core fucosylation of SPARC in cell–matrix communication and contribution to the abnormal alveolar structures in COPD.

Original languageEnglish
Article number348
JournalCellular and Molecular Life Sciences
Volume79
Issue number7
DOIs
StatePublished - 07 2022
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2022, The Author(s).

Keywords

  • COPD
  • Collagen
  • Core-fucosylation
  • Fut8
  • Matricellular protein
  • SPARC

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