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Target lysis by cholesterol extraction is a rate limiting step in the resolution of phagolysosomes

Authors :
Dante Barreda
Sergio Grinstein
Spencer A. Freeman
Source :
European Journal of Cell Biology, Vol 103, Iss 1, Pp 151382- (2024)
Publication Year :
2024
Publisher :
Elsevier, 2024.

Abstract

The ongoing phagocytic activity of macrophages necessitates an extraordinary capacity to digest and resolve incoming material. While the initial steps leading to the formation of a terminal phagolysosome are well studied, much less is known about the later stages of this process, namely the degradation and resolution of the phagolysosomal contents. We report that the degradation of targets such as splenocytes and erythrocytes by phagolysosomes occurs in a stepwise fashion, requiring lysis of their plasmalemmal bilayer as an essential initial step. This is achieved by the direct extraction of cholesterol facilitated by Niemann-Pick protein type C2 (NPC2), which in turn hands off cholesterol to NPC1 for export from the phagolysosome. The removal of cholesterol ulimately destabilizes and permeabilizes the membrane of the phagocytic target, allowing access of hydrolases to its internal compartments. In contrast, we found that saposins, which activate the hydrolysis of sphingolipids, are required for lysosomal tubulation, yet are dispensable for the resolution of targets by macrophages. The extraction of cholesterol by NPC2 is therefore envisaged as rate-limiting in the clearance of membrane-bound targets such as apoptotic cells. Selective cholesterol removal appears to be a primary mechanism that enables professional phagocytes to distinguish the target membrane from the phagolysosomal membrane and may be conserved in the resolution of autolysosomes.

Details

Language :
English
ISSN :
01719335 and 20420595
Volume :
103
Issue :
1
Database :
Directory of Open Access Journals
Journal :
European Journal of Cell Biology
Publication Type :
Academic Journal
Accession number :
edsdoj.f07f20a17f20420595cd112d07adbcb7
Document Type :
article
Full Text :
https://doi.org/10.1016/j.ejcb.2023.151382