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

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.

Core fucosylation regulates alveolar epithelial cells senescence through activating of transforming growth factor-β pathway in pulmonary fibrosis

“…Furthermore, upregulation of sialylation and fucosylation may reduce EGFR-mediated lung cancer cell invasion [ 32 ]. In lung tissues with COPD, collagen loss and reduction in CF were detected [ 33 ]. In this study, we implied that CF modifications accompany AECs senescence in pulmonary fibrosis.…”

The Multifaceted Role of FUT8 in Tumorigenesis: From Pathways to Potential Clinical Applications

“…Additionally, dysregulation of core fucosylation mediated by FUT8 is implicated in several chronic diseases. In chronic obstructive pulmonary disease, impaired core fucosylation of the secreted protein acidic and rich in cysteine results in decreased collagen binding, disrupting cell-matrix communication and leading to abnormal alveolar structures [40], while elevated FUT8 expression would activate EGFR pathway and contribute to the development of psoriasis [41]. These discoveries highlight the critical role of FUT8 in preserving the normal physiological functions of the body.…”

Targeting protein glycosylation to regulate inflammation in the respiratory tract: novel diagnostic and therapeutic candidates for chronic respiratory diseases

“…Fut8 knockout (Fut8 -/- ) mice exhibited emphysema-like changes in the lung, and Fut8 knockdown (Fut8 +/- ) mice exposed to cigarette smoke were found to be more susceptible to developing emphysema than wild-type mice ( 96 ). Knockout of FUT8 also resulted in alveolar destruction and loss of the core-fucosylated secreted protein acidic and rich in cysteine (SPARC), which impairs collagen binding ( 56 ). Decreased FUT8 activity has been correlated with poor lung function and exacerbation of COPD in patients ( 36 , 96 ).…”

“…In contrast, Fut8 -/- mice overexpressed MMPs like MMP-12 and MMP-13 and showed a dysfunctional TGF-β1 due to lack of core fucosylation, leading to downregulation of the extracellular matrix ( 99 ). As TGF-β1 plays a significant role in lung remodeling ( 100 ), the abnormal expression of FUT8 and decline in core fucosylation may affect the cell-to-matrix communication via SPARC in COPD ( 56 ). Thus, FUT8 is a potential target for developing COPD therapies as it plays an important role in the COPD development and progression through its effects on the core fucosylation of various proteins, including TGF-β1 and SPARC.…”