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

Lena Wartosch^*,, Jens C. Fuhrmann^*,1, Michaela Schweizer, Tobias Stauber^* and Thomas J. Jentsch^*,2

^* Leibniz-Institut für Molekulare Pharmakologie (FMP) and Max-Delbrück-Centrum für Molekulare Medizin (MDC), Berlin, Germany;

Freie Universität, Berlin, Germany; and

Zentrum für Molekulare Neurobiologie (ZMNH), Universität Hamburg, Hamburg, Germany

² Correspondence: Leibniz-Institut für Molekulare Pharmakologie and Max-Delbrück-Centrum für Molekulare Medizin, Robert-Rössle-Str. 10, D-13125 Berlin, Germany. E-mail: jentsch{at}fmp-berlin.de

Mutations in either ClC-7, a late endosomal/lysosomal member of the CLC family of chloride channels and transporters, or in its β-subunit Ostm1 cause osteopetrosis and lysosomal storage disease in mice and humans. The severe phenotype of mice globally deleted for ClC-7 or Ostm1 and the absence of storage material in cultured cells hampered investigations of the mechanism leading to lysosomal pathology in the absence of functional ClC-7/Ostm1 transporters. Tissue-specific ClC-7-knockout mice now reveal that accumulation of storage material occurs cell-autonomously in neurons or renal proximal tubular cells lacking ClC-7. Almost all ClC-7-deficient neurons die. The activation of glia is restricted to brain regions where ClC-7 has been inactivated. The effect of ClC-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 ClC-7 in proximal tubules allowed a direct comparison of the handling of endocytosed protein between cells expressing or lacking ClC-7. Whereas protein was endocytosed similarly in cells of either genotype, its half-life increased significantly in ClC-7-deficient cells. These experiments demonstrate that lysosomal pathology is a cell-autonomous consequence of ClC-7 disruption and that ClC-7 is important for lysosomal protein degradation.—Wartosch, L., Fuhrmann, J. C., Schweizer, M., Stauber, T., Jentsch, T. J. Lysosomal degradation of endocytosed proteins depends on the chloride transport protein ClC-7.

Key Words: neurodegeneration • neuronal ceroid lipofuscinosis • NCL • lysosomal storage disease