Journal
NATURE CELL BIOLOGY
Volume 21, Issue 10, Pages 1234-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41556-019-0394-2
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Funding
- Connaught International Scholarship for Doctoral Students from the University of Toronto
- National Council for Science and Technology/Consejo Nacional de Ciencia y Tecnologia (CONACYT) of Mexico
- Canadian Institutes of Health Research [FDN-143202]
- Gordon and Betty Moore Foundation
- Howard Hughes Medical Institute
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Phosphoinositides have a pivotal role in the maturation of nascent phagosomes into microbicidal phagolysosomes. Following degradation of their contents, mature phagolysosomes undergo resolution, a process that remains largely uninvestigated. Here we studied the role of phosphoinositides in phagolysosome resolution. Phosphatidylinositol-4-phosphate (PtdIns(4)P), which is abundant in maturing phagolysosomes, was depleted as they tubulated and resorbed. Depletion was caused, in part, by transfer of phagolysosomal PtdIns(4) P to the endoplasmic reticulum, a process mediated by oxysterol-binding protein-related protein 1L (ORP1L), a RAB7 effector. ORP1L formed discrete tethers between the phagolysosome and the endoplasmic reticulum, resulting in distinct regions with alternating PtdIns(4) P depletion and enrichment. Tubules emerged from PtdIns(4) P-rich regions, where ADP-ribosylation factor-like protein 8B (ARL8B) and SifA- and kinesin-interacting protein/pleckstrin homology domain-containing family M member 2 (SKIP/PLEKHM2) accumulated. SKIP binds preferentially to monophosphorylated phosphoinositides, of which PtdIns(4) P is most abundant in phagolysosomes, contributing to their tubulation. Accordingly, premature hydrolysis of PtdIns(4) P impaired SKIP recruitment and phagosome resolution. Thus, resolution involves phosphoinositides and tethering of phagolysosomes to the endoplasmic reticulum.
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