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

• 成果类型: Article
• 署名作者: Chadwick, Sarah R.; Barreda, Dante; Wu, Jing Ze; Ye, Gang; Yusuf, Bushra; Ren, Dejian; Hilgemann, Donald
• 署名单位: University of Toronto; Hospital for Sick Children (SickKids); University of Toronto; University of Toronto; University of Pennsylvania
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11899
• DOI: 10.1073/pnas.2309465121
• 发表日期: 2024-02-20
• 关键词: cholesterol egress; membrane tension; late endosomes; lysosomes; transport; npc1; macrophages; maturation; proteins; fusion

摘要

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.