Nature Cell Biology ( IF 17.3 ) Pub Date : 2022-05-19 , DOI: 10.1038/s41556-022-00912-0 Mariia Zeziulia 1, 2, 3 , Sandy Blin 1, 2 , Franziska W Schmitt 1, 2, 4 , Martin Lehmann 1 , Thomas J Jentsch 1, 2, 5
Intracellular organelles change their size during trafficking and maturation. This requires the transport of ions and water across their membranes. Macropinocytosis, a ubiquitous form of endocytosis of particular importance for immune and cancer cells, generates large vacuoles that can be followed optically. Shrinkage of macrophage macropinosomes depends on TPC-mediated Na+ efflux and Cl− exit through unknown channels. Relieving osmotic pressure facilitates vesicle budding, positioning osmotic shrinkage upstream of vesicular sorting and trafficking. Here we identify the missing macrophage Cl− channel as the proton-activated Cl− channel ASOR/TMEM206. ASOR activation requires Na+-mediated depolarization and luminal acidification by redundant transporters including H+-ATPases and CLC 2Cl−/H+ exchangers. As corroborated by mathematical modelling, feedback loops requiring the steep voltage and pH dependencies of ASOR and CLCs render vacuole resolution resilient towards transporter copy numbers. TMEM206 disruption increased albumin-dependent survival of cancer cells. Our work suggests a function for the voltage and pH dependence of ASOR and CLCs, provides a comprehensive model for ion-transport-dependent vacuole maturation and reveals biological roles of ASOR.
中文翻译:
质子门控阴离子转运控制大胞质体收缩
细胞内细胞器在运输和成熟过程中会改变其大小。这需要离子和水穿过它们的膜。巨胞饮作用是一种普遍存在的内吞作用形式,对免疫细胞和癌细胞特别重要,它会产生大的液泡,这些液泡可以进行光学追踪。巨噬细胞巨噬细胞体的收缩取决于 TPC 介导的 Na +流出和 Cl -通过未知通道排出。降低渗透压有助于囊泡出芽,将渗透压收缩定位在囊泡分选和运输的上游。在这里,我们将缺失的巨噬细胞 Cl -通道识别为质子激活的 Cl -通道 ASOR/TMEM206。ASOR激活需要Na +-通过冗余转运蛋白介导的去极化和管腔酸化,包括 H + -ATP 酶和 CLC 2Cl - /H +交换剂。正如数学模型所证实的那样,需要 ASOR 和 CLC 的陡峭电压和 pH 依赖性的反馈回路使液泡分辨率对转运蛋白拷贝数具有弹性。TMEM206破坏增加了癌细胞的白蛋白依赖性存活。我们的工作提出了 ASOR 和 CLC 的电压和 pH 依赖性函数,为离子传输依赖性液泡成熟提供了一个综合模型,并揭示了 ASOR 的生物学作用。