Microglia, the immune cells that protect our brain, are thought to maintain a healthy brain environment by removing unwanted substances through dynamic remodeling of the actin cytoskeleton, the cell's internal framework. It has been known that microglia express Hv1/VSOP, a channel protein that transports protons, but it was believed to function at the cell membrane surface, regulating pH in its vicinity.
Our research group has now revealed that Hv1 functions not only at the cell surface but also on endosomes, transport vesicles known to carry substances inside cells. First, by combining advanced microscopy with endosome patch-clamp techniques—a highly sensitive method capable of directly measuring ion flow from microscopic membrane structures inside cells—we demonstrated that Hv1 actually functions as a proton channel on endosomes.
Furthermore, analysis of microglia lacking Hv1 showed that the actin cytoskeleton elongated excessively, disrupting cell shape and internal structure. This suggested that Hv1 functions as a brake that suppresses actin elongation. Detailed biochemical analysis revealed that Hv1 interacts with CAPZ, a protein that binds to actin filament ends, appropriately suppressing actin cytoskeleton growth. Additionally, real-time observation of living cells successfully captured endosomes carrying Hv1 binding to the tips of actin filaments. These results demonstrate a new cellular control mechanism in which ion channels on endosomes are physically involved in the formation and arrangement of the cell skeleton.
Proceedings of the National Academy of Sciences