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质子门控阴离子转运调控巨胞饮泡回缩。

Proton-gated anion transport governs macropinosome shrinkage.

机构信息

Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany.

Max-Delbrück-Centrum für Molekulare Medizin (MDC), Berlin, Germany.

出版信息

Nat Cell Biol. 2022 Jun;24(6):885-895. doi: 10.1038/s41556-022-00912-0. Epub 2022 May 19.

DOI:10.1038/s41556-022-00912-0
PMID:35590106
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9203271/
Abstract

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.

摘要

细胞内细胞器在运输和成熟过程中会改变其大小。这需要离子和水跨膜运输。吞噬作用是一种普遍存在的胞吞作用形式，对免疫细胞和癌细胞尤为重要，它会产生可以通过光学方法跟踪的大空泡。巨噬细胞吞噬体的收缩依赖于 TPC 介导的 Na 外流和未知通道的 Cl 外流。解除渗透压有助于囊泡出芽，将渗透收缩置于囊泡分拣和运输的上游。在这里，我们确定缺失的巨噬细胞 Cl 通道是质子激活的 Cl 通道 ASOR/TMEM206。ASOR 的激活需要 Na 介导的去极化和冗余转运体（包括 H-ATP 酶和 CLC 2Cl/H 交换器）通过内腔酸化来实现。数学建模证实，需要 ASOR 和 CLCs 的陡峭电压和 pH 依赖性的反馈回路使空泡分辨率对转运体拷贝数具有弹性。TMEM206 的破坏增加了依赖白蛋白的癌细胞的存活率。我们的工作表明 ASOR 和 CLCs 的电压和 pH 依赖性具有功能，为离子转运依赖性空泡成熟提供了一个全面的模型，并揭示了 ASOR 的生物学作用。

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