Mistargeting of lysosomal enzymes in M(r) 46,000 mannose 6-phosphate receptor-deficient mice is compensated by carbohydrate-specific endocytotic receptors.

Targeted disruption of the M(r) 46,000 mannose 6-phosphate receptor (MPR 46) in mice is associated with normal levels of lysosomal enzymes in the circulation, while in MPR 46-deficient cells an increased secretion of lysosomal enzymes is apparent [Köster, A., Saftig, P., Matzner, U., von Figura, K., Peters, C. & Pohlmann, R. (1993) EMBO J. 12, 5219-5223]. This points to the existence of mechanisms that prevent or compensate for mistargeting of lysosomal enzymes in vivo. In the present study, we have injected inhibitors of three carbohydrate-specific endocytotic receptors into MPR 46-deficient and control mice. Inhibition of these receptors was associated with a pronounced increase of three lysosomal enzymes in the serum of MPR 46-deficient mice. These results clearly show that lysosomal enzymes are mistargeted in MPR 46-deficient mice and that carbohydrate-specific endocytotic receptors are part of the mechanisms that compensate for the mistargeting of lysosomal enzymes in MPR 46-deficient mice. Moreover, evidence was obtained that, also in control mice, the steady-state level of some lysosomal enzyme is controlled by these receptors.