内膜系统
细胞生物学
张力(地质)
化学
生物
生物物理学
材料科学
高尔基体
内质网
冶金
极限抗拉强度
作者
Sarah R. Chadwick,Dante Barreda,Jing Ze Wu,Gang Ye,Bushra Yusuf,Dejian Ren,Spencer A. Freeman
标识
DOI:10.1073/pnas.2309465121
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.
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