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乳酸传感器NDRG3通过与合成素-5-5的长异形相互作用,减缓了ER-to-Golgi运输

Pia E Ferle¹, Niklas Krause¹, Judith Koliwer¹

¹Faculty of Chemistry, Biochemistry III (BCIII), University of Bielefeld, Bielefeld 33615, Germany.

Proceedings of the National Academy of Sciences of the United States of America

|November 18, 2025

概括

乳酸和缺氧传感器NDRG3蛋白通过与SNARE复合体结合来负面调节ER-to-Golgi贩运. 这一发现将细胞应激,包括缺氧和乳酸,与分泌通路中的膜运输受损联系起来.

科学领域:

细胞生物学细胞生物学
分子生物学分子生物学
生物化学生物化学

背景情况:

在BET1,GOSR2和STX5的遗传变异与严重的遗传性疾病有关.
这些蛋白质与Sec22b一起,形成一个SNARE复合体,对ER衍生的囊泡与ER-Golgi中间体和cis-Golgi的融合至关重要.
虽然SCFD1/Sly1蛋白加速了这个过程,但在细胞压力下对ER-to-Golgi贩运的下调仍然不太了解.

研究的目的:

在细胞压力下识别ER-to-Golgi贩运的新型调节者.
调查乳酸和缺氧在调节膜贩运中的作用.
阐明细胞应激影响分泌途径的机制.

主要方法:

蛋白与蛋白相互作用研究,以确定NDRG3作为ER-to-Golgi SNARE复合物的结合伙伴.
生物化学测试以表征NDRG3和Stx5.5之间的结合接口.
使用NDRG3缺乏细胞进行细胞实验,以评估ER-to-Golgi在低氧和乳酸水平升高的情况下对ER-to-Golgi贩运的影响.

主要成果:

NDRG3被确定为ER-to-Golgi SNARE综合体的有约束力的合作伙伴.
NDRG3与长异形Stx5的N终端域结合,抑制了ER到Golgi的贩运.
低氧和乳酸诱导的ER-to-Golgi贩运的抑制在NDRG3缺乏的细胞中被取消.

结论:

NDRG3 作为 ER-to-Golgi SNARE 复合体功能的负调节者.
NDRG3 机械地将细胞缺氧和细胞内乳酸盐水平的升高与膜贩运的调节联系在一起.
这项研究揭示了一条新的途径,将新陈代谢状态和细胞压力连接到分泌途径.

关键词:

斯纳雷 (Snare) 是一个小鸟.遗传性肌肉衰竭是一种先天性肌肉衰竭.缺氧缺氧是指缺氧的情况.乳酸乳酸是一种乳酸.合成素-5-5的使用方法

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