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.
摘要:
粘液淤滞是粘液阻塞性疾病的病理标志,包括囊性纤维化(CF)。粘蛋白,粘液的主要成分,被羟基(O)连接的聚糖广泛修饰,主要由唾液酸终止。唾液酸是带负电荷的单糖,有助于粘蛋白的生化/生物物理特性。报告表明,粘蛋白唾液酸化可能在CF中发生改变;然而,唾液酸化减少对粘液清除的影响尚未完全确定。这里,我们研究了唾液酸化减少对最突出的气道粘蛋白的电荷状态和构象的影响,MUC5B,并定义了唾液酸化减少对粘膜纤毛运输(MCT)的功能后果。减少的唾液酸化有助于较低的带电MUC5B形式和降低的聚合物膨胀。在原代人支气管上皮细胞和大鼠气道中抑制总粘蛋白唾液酸化从头受损的MCT,和特定的α-2,3唾液酸化阻断足以概括这些发现。最后,我们显示,ST3β-半乳糖苷α-2,3-唾液酸转移酶(ST3Gal1)表达在CF中下调,并通过Elexacaftor/Tezacaftor/Ivacaftor治疗纠正CFTR而部分恢复.总的来说,这项研究证明了粘蛋白唾液酸化在粘液清除中的重要性,并确定ST3Gal1减少的唾液酸化是CF和潜在的其他粘膜阻塞性疾病的可能治疗靶标.