1. Formation of a giant unilocular vacuole via macropinocytosis-like process confers anoikis resistance.
- Author
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Kim J, Kim D, Kim DK, Lee SH, Jang W, and Lim DS
- Subjects
- Animals, Humans, Actin Cytoskeleton metabolism, Time-Lapse Imaging, Cell Survival, Extracellular Matrix metabolism, Vacuoles metabolism, Anoikis physiology, Pinocytosis physiology, Actins metabolism
- Abstract
Cell survival in metazoans depends on cell attachment to the extracellular matrix (ECM) or to neighboring cells. Loss of such attachment triggers a type of programmed cell death known as anoikis, the acquisition of resistance to which is a key step in cancer development. The mechanisms underlying anoikis resistance remain unclear, however. The intracellular F-actin cytoskeleton plays a key role in sensing the loss of cell-ECM attachment, but how its disruption affects cell fate during such stress is not well understood. Here, we reveal a cell survival strategy characterized by the formation of a giant unilocular vacuole (GUVac) in the cytoplasm of the cells whose actin cytoskeleton is disrupted during loss of matrix attachment. Time-lapse imaging and electron microscopy showed that large vacuoles with a diameter of >500 nm accumulated early after inhibition of actin polymerization in cells in suspension culture, and that these vacuoles subsequently coalesced to form a GUVac. GUVac formation was found to result from a variation of a macropinocytosis-like process, characterized by the presence of inwardly curved membrane invaginations. This phenomenon relies on both F-actin depolymerization and the recruitment of septin proteins for micron-sized plasma membrane invagination. The vacuole fusion step during GUVac formation requires PI(3)P produced by VPS34 and PI3K-C2α on the surface of vacuoles. Furthermore, its induction after loss of matrix attachment conferred anoikis resistance. Our results thus show that the formation of a previously unrecognized organelle promotes cell survival in the face of altered actin and matrix environments., Competing Interests: JK, DK, DK, SL, WJ, DL No competing interests declared, (© 2024, Kim, Kim et al.)
- Published
- 2024
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