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

Item Type:	Article
Title:	Lysosomal degradation of endocytosed proteins depends on the chloride transport protein ClC-7
Creators Name:	Wartosch, L. and Fuhrmann, J.C. and Schweizer, M. and Stauber, T. and Jentsch, T.J.
Abstract:	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, L., Fuhrmann, J. C., Schweizer, M., Stauber, T., Jentsch, T. J. Lysosomal degradation of endocytosed proteins depends on the chloride transport protein ClC-7.
Keywords:	Neurodegeneration, Neuronal Ceroid Lipofuscinosis, NCL, Lysosomal Storage Disease, Animals, Mice
Source:	FASEB Journal
ISSN:	0892-6638
Publisher:	Federation of American Societies for Experimental Biology
Volume:	23
Number:	12
Page Range:	4056-4068
Date:	December 2009
Official Publication:	https://doi.org/10.1096/fj.09-130880
PubMed:	View item in PubMed

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