乳酸驱动的ATP6V1B2乳化通过将 lysosomal 功能障碍与线粒体 ROS 依赖性 pyroptosis 联系起来,引发了喘性炎症
Qiaoyun Bai1, Ningpo Ding1, Rixin Feng1
1Jilin Key Laboratory for Immune and Targeting Research on Common Allergic Diseases, Yanbian University, Yanji, 133002, PR China; Department of Anatomy, Histology and Embryology, Yanbian University Medical College, Yanji, 133002, PR China.
Redox biology
|February 4, 2026
概括
乳酸积累通过乳化ATP6V1B2驱动喘,导致细胞损伤和热亡. 在喘模型中,阻断这种乳糖化会降低呼吸道炎症和热.
科学领域:
- 免疫学 免疫学 免疫学
- 代谢途径 代谢途径
- 细胞生物学 细胞生物学
背景情况:
- 免疫代谢重编程驱动了喘病因的产生.
- 乳酸,呼吸道炎症和蛋白质乳酸化 (Kla) 之间的分子联系尚不清楚.
- ATP6V1B2 是一个关键的V-ATPase亚单元,涉及到细胞过程.
研究的目的:
- 通过蛋白质乳化阐明将乳酸积累与呼吸道炎症联系起来的分子机制.
- 为了确定喘中关键的乳化点.
- 为了研究ATP6V1B2乳化在喘发病过程中的作用.
主要方法:
- 室内灰尘虫 (HDM) 诱导的喘模型.
- 定量乳酸组学. 定量乳酸组学.
- 分子动力学模拟和生物化学分析.
- 在初级人类支气管上皮细胞 (HBEs) 中进行验证.
- 在体内研究使用AAV输出的乳化缺陷突变体.
主要成果:
- ATP6V1B2被确定为核心乳化标,乳化发生在K108/K109.
- 乳化限制ATP6V1B2的灵活性,分解V1-V0复合体,并损害质子活动.
- 这导致溶酶体化,膜通透性 (LMP),线粒体ROS爆发,并通过Caspase-8/3/GSDME通路进行灭.
- 在体内阻断ATP6V1B2乳化减弱了呼吸道炎症,Th2细胞因子的释放和热.
结论:
- 一个新的"l-乳酸盐-ATP6V1B2-GSDME"轴的特征.
- ATP6V1B2乳化作为关键的代谢开关,将溶酶体损伤与炎症细胞死亡联系起来.
- 向ATP6V1B2乳化为严重慢性喘中代谢失调提供了一个潜在的治疗策略.
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