控制P4-ATPase对氏体膜不对称性和新菌素耐药性的控制
Bhawik K Jain1,2, H Diessel Duan3,2, Christina Valentine1
1Department of Biological Sciences, Vanderbilt University, Nashville, TN, USA.
bioRxiv : the preprint server for biology
|March 17, 2025
概括
尼奥米辛抗生素进入细胞是由细胞外的酸-4-酸盐 (PI4P) 介导的. 这种酸通过内细胞网膜和戈尔吉细胞被运输,从而影响菌素敏感性和细胞信号传递.
科学领域:
- 细胞生物学 细胞生物学
- 生物化学 生物化学
- 分子生物学分子生物学
背景情况:
- 尼奥米是一种氨基糖化物抗生素,表现出强大的抗菌作用,但受到毒性和耳毒性限制.
- 进入真核细胞中菌素吸收的精确机制尚未完全阐明.
- 酵母中的脂翻酶Neo1对于菌素耐药性和维持膜不对称性至关重要.
研究的目的:
- 为了研究Neo1和酸-4-酸盐 (PI4P) 在菌素敏感性中的作用.
- 阐明PI4P的输送途径及其对氨基糖化物吸收的影响.
- 了解酸的恒常性和细胞外酸信号传递的机制.
主要方法:
- 在酵母中对Neo1突变进行遗传分析,以评估neomycin敏感性.
- 在人体细胞中对ATP9A的抑制,以评估其在细胞外PI4P暴露中的作用.
- 低温电子显微镜 (Cryo-EM) 可视化PI4P与Neo1.1的结合.
- 调查PI4P的非膀运输 (Osh6) 和膀运输 (COPII).
主要成果:
- 在Neo1的突变导致neomycin过敏通过暴露PI4P在细胞表面.
- 人类ATP9A的淘汰也导致细胞外PI4P暴露,并与菌素敏感性相关.
- PI4P的运输涉及内质网膜,戈尔吉和非膀/膀运输通路.
- 化EM证实PI4P在Neo1的转位途径中的结合.
- 戈尔吉中Neo1功能的丧失导致PI4P的分泌,作为neomycin受体.
结论:
- 细胞外PI4P作为neomycin的受体,促进其内细胞吸收,并影响氨基糖化物敏感性.
- 这项研究揭示了氏酸盐的恒温和PI4P传输的新机制.
- 这些发现突显了细胞外化在细胞信号传递和药物吸收中的作用.
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