MGAT3的缺失增强TGF-β信号传导，促进闭塞性细支气管炎的进展
Loss of MGAT3 Amplifies TGF-β Signaling to Promote Bronchiolitis Obliterans Progression.
摘要(中文译文)
闭塞性细支气管炎综合征（BOS）是异基因造血干细胞移植（allo-HSCT）后的一种严重并发症，表现为以小气道上皮炎症和纤维化为特征的慢性移植物抗宿主病。这种进行性纤维化阻塞细支气管气道，导致患者出现呼吸窘迫。由于缺乏有效治疗手段，深入理解其潜在机制至关重要。本研究探讨了BOS中异常糖基化调控的分子机制，旨在为该疾病的早期诊断和治疗提供新思路。收集接受allo-HSCT后伴或不伴BOS患者的支气管肺泡灌洗液（BALF）。采用固相萃取法富集BALF中的N-聚糖。使用基质辅助激光解吸/电离飞行时间质谱（MALDI-TOF/TOF-MS）检测BOS患者BALF中的N-糖基化特征。利用移植物抗宿主病（GVHD）小鼠模型验证该现象。随后通过慢病毒转染检测MGAT3敲低对气道上皮细胞（BEAS-2B）生物学功能的影响。采用蛋白质印迹、酶联免疫吸附试验（ELISA）和免疫荧光（IF）探讨MGAT3缺失增强TGF-β信号传导的分子机制。本研究考察了BOS患者BALF中N-糖基化的变化，发现平分型GlcNAc N-聚糖的缺失与BOS进展之间存在强相关性。我们发现了一种新机制，即合成平分型GlcNAc结构的酶MGAT3对TGF-β信号传导具有关键调控作用。MGAT3和平分型GlcNAc的缺失通过上调潜伏型TGF-β结合蛋白1（LTBP1）增加TGF-β储存，并通过增加TGF-β受体的可利用性，显著增强TGF-β信号传导。我们的发现凸显了异常糖基化在BOS进展中的关键作用，对于开发早期诊断的新型生物标志物、确定新的治疗靶点以及最终改善BOS患者的生活质量具有重要前景。
Abstract
Bronchiolitis obliterans syndrome (BOS), a severe complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT), presents as chronic graft-versus-host disease characterized by inflammation and fibrosis of the small airway epithelium. This progressive fibrosis obstructs bronchiolar airways, leading to respiratory distress in patients. Due to the lack of effective treatments, a deeper understanding of the underlying mechanisms is crucial. This study explored the molecular mechanisms underlying the abnormal glycosylation regulation in BOS, aiming to provide new insights for early diagnosis and treatment of this disease. Bronchoalveolar lavage fluid (BALF) was collected from patients with and without BOS following allo-HSCT. N-glycans from the BALF were enriched using a solid-phase extraction method. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF/TOF-MS) was used to detect N-glycosylation characteristics in the BALF of BOS patients. This phenomenon was validated using a graft-versus-host disease (GVHD) mouse model. The impact of MGAT3 knockdown on the biological functions of airway epithelial cells (BEAS-2B) was then examined using lentivirus transfection. The molecular mechanism by which the loss of MGAT3 enhances TGF-β signaling was explored using western blotting, enzyme-linked immunosorbent assay (ELISA), and immunofluorescence (IF). Our study investigated N-glycosylation changes in BALF of BOS patients and identified a strong correlation between the loss of bisecting-GlcNAc N-glycans and BOS progression. We found a novel mechanism where MGAT3, the enzyme synthesizing bisecting-GlcNAc structures, critically regulates TGF-β signaling. MGAT3 and bisecting-GlcNAc deficiency significantly enhance TGF-β signaling by increasing TGF-β storage through upregu-lation of latent TGF-β binding protein 1 (LTBP1) and by increasing the availability of TGF-β receptors. Our discovery highlights the crucial role of aberrant glycosylation in BOS progression and holds significant promise for developing novel biomarkers for early diagnosis, identifying new therapeutic targets, and ultimately improving the quality of life for BOS patients.
如何引用
AMA
Wei Ge, Jing Li, Yan Chen, Daxiong Zeng, Shuang Yang, Junhong Jiang. Loss of MGAT3 Amplifies TGF-β Signaling to Promote Bronchiolitis Obliterans Progression.. Clinical laboratory. 2026; doi:10.7754/Clin.Lab.2025.250831.
APA
Wei Ge, Jing Li, Yan Chen, Daxiong Zeng, Shuang Yang, Junhong Jiang (2026). Loss of MGAT3 Amplifies TGF-β Signaling to Promote Bronchiolitis Obliterans Progression.. Clinical laboratory. https://doi.org/10.7754/Clin.Lab.2025.250831
GB/T 7714
Wei Ge, Jing Li, Yan Chen, Daxiong Zeng, Shuang Yang, Junhong Jiang. Loss of MGAT3 Amplifies TGF-β Signaling to Promote Bronchiolitis Obliterans Progression.[J]. Clinical laboratory, 2026 doi:10.7754/Clin.Lab.2025.250831.
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