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J Biol Chem, Vol. 274, Issue 27, 19063-19071, July 2, 1999

Accumulation of Sialic Acid in Endocytic Compartments Interferes with the Formation of Mature Lysosomes
IMPAIRED PROTEOLYTIC PROCESSING OF CATHEPSIN B IN FIBROBLASTS OF PATIENTS WITH LYSOSOMAL SIALIC ACID STORAGE DISEASE

Johannes A. Schmid^§, Lukas Mach, Eduard Paschke^**, and Josef Glössl

From the  Centre of Applied Genetics, University of Agricultural Sciences, Vienna A-1190, the ^§ Department of Vascular Biology and Thrombosis Research, University of Vienna, Vienna A-1235, Austria, the  Biochemistry Department, University of Western Australia, Nedlands W.A. 6907, Australia, and ^** Children's Hospital, Graz A-8036, Austria

The impact of an altered endocytic environment on the biogenesis of lysosomes was studied in fibroblasts of patients suffering from sialic acid storage disease (SASD). This inherited disorder is characterized by the accumulation of acidic monosaccharides in lysosomal compartments and a concomitant decrease of their buoyant density. We demonstrate that C-terminal trimming of the lysosomal cysteine proteinase cathepsin B is inhibited in SASD fibroblasts. This late event in the biosynthesis of cathepsin B normally takes place in mature lysosomes, suggesting an impaired biogenesis of these organelles in SASD cells. When normal fibroblasts are loaded with sucrose, which inhibits transport from late endosomes to lysosomes, C-terminal cathepsin B processing is prevented to the same extent. Further characterization of the terminal endocytic compartments of SASD cells revealed properties usually associated with late endosomes/prelysosomes. In addition to a decreased buoyant density, SASD "lysosomes" show a reduced acidification capacity and appear smaller than their normal counterparts. We conclude that the accumulation of small non-diffusible compounds within endocytic compartments interferes with the formation of mature lysosomes and that the acidic environment of the latter organelles is a prerequisite for C-terminal processing of lysosomal hydrolases.

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Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.

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