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

Mutations in ClC-7, a late endosomal/lysosomal member of the CLC family of chloride channels and transporters1,2, cause osteopetrosis3 and lysosomal storage disease4 in humans and mice. Severe osteopetrosis is also observed with mutations in the OSTM1 gene, which encodes a membrane protein of unknown function5. 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 β–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 mice4, show lysosomal storage and neurodegeneration in addition to osteopetrosis implies a more general importance for ClC-7–Ostm1 complexes.