Abnormal lysosomal sorting with an enhanced secretion of cathepsin D precursor molecules bearing monoester phosphate groups.
It has been reported that besides defects in the phosphorylation such as in the I-cell disease, a failure in the uncovering of mannose 6-phosphate residues may result in an increase of lysosomal enzyme activities in serum [Alexander et al., Hum. Genet. 73, 53-59 (1986)]. We examined fibroblasts that were derived from the original biopsy, observed an enhanced secretion of lysosomal enzymes including cathepsin D, but found that both the phosphorylation and uncovering of mannose 6-phosphate residues were normal. The enhanced secretion of cathepsin D was characterized by an increase in the secretion of phosphorylated molecules that were sensitive to a treatment with alkaline phosphatase. The enhanced secretion of the phosphatase-sensitive form of procathepsin D was further increased in the presence of antibodies directed to cation-independent mannose 6-phosphate receptors. In contrast, antibodies specific to cation-dependent mannose 6-phosphate receptors selectively inhibited the secretion of the phosphatase-sensitive procathepsin D molecules. A chromatographic analysis of oligosaccharides from the secreted procathepsin D confirmed that the cells secrete proenzyme molecules rich in oligosaccharides with two uncovered phosphate residues. It is suggested that the enhanced secretion of procathepsin D in the variant fibroblasts results from an abnormal sorting rather than processing of phosphorylated lysosomal enzymes.
Faulhaber
J
J
Institut für Physiologische Chemie der Philipps-Universität Marburg, Germany.
Fensom
A
A
Hasilik
A
A
D002402:Cathepsin D / Q000378:metabolism*; D002460:Cell Line; D004792:Enzyme Precursors / Q000378:metabolism*; D006801:Humans; D008247:Lysosomes / Q000201:enzymology; D010710:Phosphates / Q000378:metabolism; D017527:Receptor, IGF Type 2 / Q000502:physiology; D001619:beta-N-Acetylhexosaminidases / Q000378:metabolism
D004792:Enzyme Precursors; D010710:Phosphates; D017527:Receptor, IGF Type 2; D001619:beta-N-Acetylhexosaminidases; C058345:procathepsin D; D002402:Cathepsin D