ClC-7 requires Ostm1 as a beta-subunit to support bone resorption and lysosomal function

Item Type:	Article
Title:	ClC-7 requires Ostm1 as a beta-subunit to support bone resorption and lysosomal function
Creators Name:	Lange, P.F. and Wartosch, L. and Jentsch, T.J. and Fuhrmann, J.C.
Abstract:	Mutations in ClC-7, a late endosomal/lysosomal member of the CLC family of chloride channels and transporters, cause osteopetrosis and lysosomal storage disease in humans and mice. Severe osteopetrosis is also observed with mutations in the OSTM1 gene, which encodes a membrane protein of unknown function. Here we show that both ClC-7 and Ostm1 proteins co-localize in late endosomes and lysosomes of various tissues, as well as in the ruffled border of bone-resorbing osteoclasts. Co-immunoprecipitations show that ClC-7 and Ostm1 form a molecular complex and suggest that Ostm1 is a beta-subunit of ClC-7. ClC-7 is required for Ostm1 to reach lysosomes, where the highly glycosylated Ostm1 luminal domain is cleaved. Protein but not RNA levels of ClC-7 are greatly reduced in grey-lethal mice, which lack Ostm1, suggesting that the ClC-7-Ostm1 interaction is important for protein stability. As ClC-7 protein levels in Ostm1-deficient tissues and cells, including osteoclasts, are decreased below 10% of normal levels, Ostm1 mutations probably cause osteopetrosis by impairing the acidification of the osteoclast resorption lacuna, which depends on ClC-7 (ref. 3). The finding that grey-lethal mice, just like ClC-7-deficient mice, show lysosomal storage and neurodegeneration in addition to osteopetrosis implies a more general importance for ClC-7-Ostm1 complexes.
Keywords:	Bone Resorption, Chloride Channels, Gene Deletion, Lysosomes, Membrane Proteins, Phenotype, Protein Binding, Protein Subunits, Protein Transport, Animals, Mice
Source:	Nature
ISSN:	0028-0836
Publisher:	Nature Publishing Group
Volume:	440
Number:	7081
Page Range:	220-223
Date:	9 March 2006
Official Publication:	https://doi.org/10.1038/nature04535
PubMed:	View item in PubMed

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