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Proton-gated anion transport governs macropinosome shrinkage

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Item Type:Article
Title:Proton-gated anion transport governs macropinosome shrinkage
Creators Name:Zeziulia, M. and Blin, S. and Schmitt, F.W. and Lehmann, M. and Jentsch, T.J.
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.
Keywords:Anions, Chloride Channels, Hydrogen-Ion Concentration, Ion Transport, Protons
Source:Nature Cell Biology
Publisher:Nature Publishing Group
Page Range:885-895
Date:June 2022
Official Publication:https://doi.org/10.1038/s41556-022-00912-0
PubMed:View item in PubMed

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