Mistargeting of Lysosomal Enzymes in Mr 46000 Mannose 6‐phosphate Receptor‐deficient Mice is Compensated by Carbohydrate‐specific Endocytotic Receptors

Abstract

Targeted disruption of the M, 46000 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. Copyright © 1994, Wiley Blackwell. All rights reserved