Sorting nexin 10 regulates lysosomal ionic homeostasis via ClC-7 by controlling PI(3,5)P2

Area of Science:

• Cell Biology
• Molecular Biology
• Biochemistry

Background:

• Snx10 (Sorting Nexin 10) mutations are linked to neurodegeneration, blindness, and osteopetrosis.
• Osteoclasts and macrophages share functional similarities, particularly in phagocytosis.
• The role of Snx10 in phagocytosis and lysosomal function remained largely unexplored.

Purpose of the Study:

• To investigate the function of Snx10 in phagocytosis and phagosome resolution.
• To elucidate the molecular mechanism by which Snx10 influences phagolysosomal function.

Main Methods:

• Analysis of Snx10-deficient cells (likely mouse models or cell lines).
• Assessment of phagosome resolution and (phago)lysosomal function.
• Measurement of chloride ion (Cl-) and phosphoinositide levels within (phago)lysosomes.
• Investigation of ClC-7 (a lysosomal 2Cl-/H+ antiporter) activity and localization.
• Analysis of phosphatidylinositol 3,5-bisphosphate (PI[3,5]P2) and phosphatidylinositol 3-phosphate (PI[3]P) dynamics.

Main Results:

• Deletion of Snx10 impaired phagosome resolution, characterized by reduced Cl- accumulation in (phago)lysosomes.
• This phenotype mimicked that of cells lacking ClC-7, suggesting a link between Snx10 and ClC-7 function.
• Snx10 ablation did not affect ClC-7 delivery but significantly reduced its activity.
• Snx10 regulates ClC-7 activity indirectly by controlling the availability of PI[3,5]P2, a known inhibitor of ClC-7.
• Snx10 limits PI[3,5]P2 formation by regulating the transport of its precursor, PI[3]P, to (phago)lysosomes.

Conclusions:

• Snx10 is essential for efficient phagosome resolution by enabling luminal Cl- accumulation in phagosomes and lysosomes.
• Snx10 regulates phagolysosomal Cl- homeostasis indirectly through phosphoinositide metabolism, specifically by controlling PI[3,5]P2 levels.
• These findings suggest a novel mechanism for Snx10 in regulating phagocytosis and may explain impaired bone resorption in Snx10 deficiency.