Lipid-gated monovalent ion fluxes regulate endocytic traffic and support immune surveillance

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Science  17 Jan 2020:
Vol. 367, Issue 6475, pp. 301-305
DOI: 10.1126/science.aaw9544

Ion fluxes resolve organellar volume

Animal cells continuously sample the surrounding medium, a feature accentuated in immune cells. Sampling is accomplished by trapping external medium into membrane-bound vesicles or vacuoles. These structures are promptly resolved, thus avoiding accumulation of endomembranes and volume expansion. In a variety of cultured cells, Freeman et al. found that this resolution entails conversion of spherical vacuoles into thin tubules, a process that involves marked changes in surface-to-volume ratio (see the Perspective by King and Smythe). Shrinkage of membrane-bound structures is driven by ion fluxes and subsequent osmotic transfer of water. Shriveled vacuoles attract curvature-sensing proteins that promote the extension of fine tubules. Ion channels thereby control membrane remodeling, enabling receptor recycling and proper routing of cellular cargo.

Science, this issue p. 301; see also p. 246


Despite ongoing (macro)pinocytosis of extracellular fluid, the volume of the endocytic pathway remains unchanged. To investigate the underlying mechanism, we used high-resolution video imaging to analyze the fate of macropinosomes formed by macrophages in vitro and in situ. Na+, the primary cationic osmolyte internalized, exited endocytic vacuoles via two-pore channels, accompanied by parallel efflux of Cl and osmotically coupled water. The resulting shrinkage caused crenation of the membrane, which fostered recruitment of curvature-sensing proteins. These proteins stabilized tubules and promoted their elongation, driving vacuolar remodeling, receptor recycling, and resolution of the organelles. Failure to resolve internalized fluid impairs the tissue surveillance activity of resident macrophages. Thus, osmotically driven increases in the surface-to-volume ratio of endomembranes promote traffic between compartments and help to ensure tissue homeostasis.

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