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

Mutations or ablation of Snx10 are associated with neurodegeneration, blindness, and osteopetrosis. The similarities between osteoclasts and macrophages prompted us to analyze the role of Snx10 in phagocytosis. Deletion of Snx10 impaired phagosome resolution. Defective resolution was caused by reduced Cl⁻ accumulation within (phago)lysosomes, replicating the phenotype reported in macrophages lacking ClC-7, a lysosomal 2Cl⁻/H⁺ antiporter. Delivery of ClC-7 to (phago)lysosomes was unaffected by ablation of Snx10, but its activity was markedly depressed. Snx10 was found to regulate ClC-7 activity indirectly by controlling the availability of phosphatidylinositol 3,5-bisphosphate (PI[3,5]P₂), which inhibits ClC-7. By limiting the formation of PI(3,5)P₂, Snx10 enables the accumulation of luminal Cl⁻ in phagosomes and lysosomes, which is required for their optimal degradative function. Our data suggest that Snx10 regulates the delivery of PI 3-phosphate (PI[3]P), the precursor of PI(3,5)P₂, from earlier endocytic compartments to (phago)lysosomes. By controlling the traffic of phosphoinositides, Snx10 regulates phagosomal resolution and possibly accounts for the impaired bone resorption in Snx10-deficient osteoclasts.