Lysosomal degradation of endocytosed proteins depends on the chloride transport protein C1C-7.

Mutations in either C1C-7, a late endosomal/lysosomal member of the CLC family of chloride channels and transporters, or in its β-subunit Ostml cause osteopetrosis and lysosomal storage disease in mice and humans. The severe phenotype of mice globally deleted for C1C-7 or Ostml and the absence of storage material in cultured cells hampered investigations of the mechanism leading to lysosomal pathology in the absence of functional C1C-7/Ostml transporters. Tissue-specific C1C-7-knockout mice now reveal that accumulation of storage material occurs cell-autonomously in neurons or renal proximal tubular cells lacking C1C-7. Almost all C1C-7-deficient neurons die The activation of glia is restricted to brain regions where C2C-7 has been inactivated. The effect of C1C-7 disruption on lysosomal function was investigated in renal proximal tubular cells, which display high endocytotic activity. Pulse-chase endocytosis experiments in vivo with mice carrying chimeric deletion of C1C-7 in proximal tubules allowed a direct comparison of the handling of endocytosed protein between cells expressing or lacking C1C-7. Whereas protein was endocytosed similarly in cells of either genotype, its half-life increased significantly in C1C-7-deficient cells. These experiments demonstrate that lysosomal pathology is a cell-autonomous consequence of C1C-7 disruption and that C1C-7 is important for lysosomal protein degradation. [ABSTRACT FROM AUTHOR]