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A more recent version of this article appeared on July 1, 2004
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Submitted on February 5, 2004
Revised on April 13, 2004
Accepted on April 15, 2004
1 Institute of Biochemistry, University of Kiel, Olshausenstr. 40, D-24098 Kiel, Germany
2 Cell Biology, Instituto de Investigaciones Citológicas, FVIB, Amadeo de Saboya 4, 46010 Valencia, Spain
3 Division of Pharmaceutical Cell Biology, Graduate School of Pharmaceutical Sciences, Kyushu University, Maidashi 3-1-1, Fukuoka 812-8582, Japan
4 Institute of Anatomy, University of Kiel, Olshausenstr. 40, D-24098 Kiel, Germany
5 Dept for Human Genetics CB4, K.U. Leuven, and Flanders Interuniversity Institute for Biotechnology VIB IV, Herestraat 49, B-3000 Leuven, Belgium
6 IBM II, Molecular Cell Biology, University Hospital Hamburg-Eppendorf, Martinistrasse 52, D- 20246 Hamburg, Germany
7 Dept. of Biochemistry 2, Heinrich Düker Weg 12, D-37073 Göttingen, Germany
* Corresponding author. E-mail address: psaftig{at}biochem.uni-kiel.de.
Mice double deficient in LAMP-1 and LAMP-2 were generated. The embryos died between embryonic days 14.5 and 16.5. An accumulation of autophagic vacuoles was detected in many tissues including endothelial cells and Schwann cells. Fibroblast cell lines derived from the double deficient embryos accumulated autophagic vacuoles and the autophagy protein LC3II after amino acid starvation. Lysosomal vesicles were larger and more peripherally distributed, and showed a lower specific density in Percoll gradients in double deficient when compared with control cells. Lysosomal enzyme activities, cathepsin D processing and mannose 6-phosphate receptor expression levels were not affected by the deficiency of both LAMPs. Surprisingly, LAMP-1 and LAMP-2 deficiencies did not affect long-lived protein degradation rates, including proteolysis, due to chaperone-mediated autophagy. The LAMP-1/2 double deficient cells and, to a lesser extent, LAMP-2 single deficient cells showed an accumulation of unesterified cholesterol in endo/lysosomal, rab7 and NPC1 positive compartments, as well as reduced amounts of lipid droplets. The cholesterol accumulation in LAMP-1/2 double deficient cells could be rescued by overexpression of murine LAMP-2a, but not by LAMP-1, highlighting the more prominent role of LAMP-2. Taken together these findings indicate partially overlapping functions for LAMP-1 and LAMP-2 in lysosome biogenesis, autophagy and cholesterol homeostasis.
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