| First Author | Zeziulia M | Year | 2022 |
| Journal | Nat Cell Biol | Volume | 24 |
| Issue | 6 | Pages | 885-895 |
| PubMed ID | 35590106 | Mgi Jnum | J:340914 |
| Mgi Id | MGI:7414440 | Doi | 10.1038/s41556-022-00912-0 |
| Citation | Zeziulia M, et al. (2022) Proton-gated anion transport governs macropinosome shrinkage. Nat Cell Biol 24(6):885-895 |
| abstractText | 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. |
