Alternative mechanisms for trafficking of lysosomal enzymes in mannose 6-phosphate receptor-deficient mice are cell type-specific

Viable mice nullizygous in genes encoding the 300 kDa and the 46 kDa mannos e 6-phosphate receptors (MPR 300 and MPR 46) and the insulin like growth fa ctor II (IGF II) were generated to study the trafficking of lysosomal enzym es in the absence of MPRs. The mice have an I-cell disease-like phenotype, with increase of lysosomal enzymes in serum and normal activities in tissue s. Surprisingly, the ability of MPR-deficient cells to transport newly synt hesized lysosomal enzymes to lysosomes and the underlying mechanisms were f ound to depend on the cell type. MPR-deficient thymocytes target newly synt hesized cathepsin D to lysosomes via an intracellular route. In contrast, h epatocytes and fibroblasts secrete newly synthesized cathepsin D. In fibrob lasts recapture of secreted lysosomal enzymes, including that of cathepsin D, is limited and results in lysosomal storage, both in vivo and in vitro, whereas recapture by hepatocytes is remarkably effective in vivo and can re sult in lysosomal enzyme levels even above normal.