Lysosomal degradation of endocytosed proteins depends on the chloride transport protein ClC-7.
Mutations in either ClC-7, a late endosomal/lysosomal member of the CLC family of chloride channels and transporters, or in its beta-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
Lena
L
Leibniz-Institut für Molekulare Pharmakologie and Max-Delbrück-Centrum für Molekulare Medizin, Robert-Rössle-Str. 10, D-13125 Berlin, Germany.
Fuhrmann
Jens C
JC
Schweizer
Michaela
M
Stauber
Tobias
T
Jentsch
Thomas J
TJ
D000818:Animals; D018118:Chloride Channels / Q000235:genetics* / Q000378:metabolism*; D002712:Chlorides / Q000378:metabolism; D004705:Endocytosis / Q000502:physiology*; D005838:Genotype; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011506:Proteins / Q000378:metabolism*
D018118:Chloride Channels; D002712:Chlorides; C490803:Clcn7 protein, mouse; D011506:Proteins