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| Item Type: | Article |
|---|---|
| Title: | Proton-gated anion transport governs macropinosome shrinkage |
| Creators Name: | Zeziulia, M., Blin, S., Schmitt, F.W., 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 |
| ISSN: | 1465-7392 |
| Publisher: | Nature Publishing Group |
| Volume: | 24 |
| Number: | 6 |
| 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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