乳化-YTHDF1轴促进DNAH5依赖的膜防御在Pseudomonas aeruginosa感染中
Jing Wang1,2,3, Xiang Shen1,2,3, Yanan Li1,2,3
1Department of Pulmonary and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
伪菌感染通过改变宿主代谢和RNA修饰来破坏呼吸道防御. 一个涉及YTHDF1和DNAH5的新型乳糖化-m6A通路损害了状功能,增加了细菌负担.
科学领域:
- 免疫学 免疫学 免疫学
- 分子生物学分子生物学
- 呼吸系统医学 呼吸系统医学
背景情况:
- 在呼吸道疾病中,Pseudomonas aeruginosa感染带来了重大挑战.
- 已知呼吸道上皮细胞 (AECs) 中的主体炎症反应,但表体转录体调节和代谢重编程相互作用尚不清楚.
研究的目的:
- 调查乳化-m6A轴在P. aeruginosa感染期间协调状功能和抗菌防御中的作用.
- 阐明所涉及的代谢-表观遗传协调机制.
主要方法:
- 综合体内和体外P. aeruginosa感染的模型.
- 对宿主乳酸水平,基因素乳化,m6A甲基化和YTHDF1表达的分析.
- m6A-seq用于识别甲基化mRNA点,重点是DNAH5.5.
- 有条件的YTHDF1淘汰赛小鼠模型.
主要成果:
- 菌感染会耗尽宿主乳酸,通过降低YTHDF1.1的调节,降低了基因素H3K18的乳化和随后的m6A甲基化.
- DNAH5mRNA对于纤毛细胞运动至关重要,显示出偏好的低甲基化.
- 乳化-YTHDF1-DNAH5轴对于维持纤毛节拍频率和粘膜细胞清除至关重要.
- YTHDF1缺乏导致细菌负担增加.
结论:
- 一个涉及乳酸和m6A修饰的新型代谢-表观遗传电路影响宿主对P. aeruginosa的防御.
- 微生物诱导的代谢变化重新编程RNA修改以禁用状防御.
- 针对乳酸酸-YTHDF1轴为P. aeruginosa相关的肺部疾病提供了潜在的治疗策略.
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