Two-pore channels regulate endomembrane tension to enable remodeling and resolution of phagolysosomes.

Autor:	Chadwick SR; Program in Cell Biology, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada., Barreda D; Program in Cell Biology, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada., Wu JZ; Program in Cell Biology, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.; Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada., Ye G; Program in Cell Biology, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada., Yusuf B; Program in Cell Biology, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.; Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada., Ren D; Department of Biology, University of Pennsylvania, Philadelphia, PA 19104., Freeman SA; Program in Cell Biology, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.; Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2024 Feb 20; Vol. 121 (8), pp. e2309465121. Date of Electronic Publication: 2024 Feb 14.
DOI:	10.1073/pnas.2309465121
Abstrakt:	Phagocytes promptly resolve ingested targets to replenish lysosomes and maintain their responsiveness. The resolution process requires that degradative hydrolases, solute transporters, and proteins involved in lipid traffic are delivered and made active in phagolysosomes. It also involves extensive membrane remodeling. We report that cation channels that localize to phagolysosomes were essential for resolution. Specifically, the conductance of Na + by two-pore channels (TPCs) and the presence of a Na + gradient between the phagolysosome lumen and the cytosol were critical for the controlled release of membrane tension that permits deformation of the limiting phagolysosome membrane. In turn, membrane deformation was a necessary step to efficiently transport the cholesterol extracted from cellular targets, permeabilizing them to hydrolases. These results place TPCs as regulators of endomembrane remodeling events that precede target degradation in cases when the target is bound by a cholesterol-containing membrane. The findings may help to explain lipid metabolism dysfunction and autophagic flux impairment reported in TPC KO mice and establish stepwise regulation to the resolution process that begins with lysis of the target. Competing Interests: Competing interests statement:The authors declare no competing interest.
Databáze:	MEDLINE
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