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Biological Chemistry

Editor-in-Chief: Brüne, Bernhard

Editorial Board Member: Buchner, Johannes / Lei, Ming / Ludwig, Stephan / Sies, Helmut / Turk, Boris / Wittinghofer, Alfred

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Impaired turnover of autophagolysosomes in cathepsin L deficiency

Julia Dennemärker1, 2 / Tobias Lohmüller1 / Sebastian Müller1 / Stephanie Vargas Aguilar1 / Desmond J. Tobin3 / Christoph Peters1, 4 / Thomas Reinheckel1, 4

1Institute for Molecular Medicine and Cell Research, Albert Ludwigs University Freiburg, D-79104 Freiburg, Germany

2Faculty of Biology, Albert Ludwigs University Freiburg, D-79104 Freiburg, Germany

3Centre for Skin Sciences, School of Life Sciences, University of Bradford, Bradford BD7 1DP, UK

4Centre for Biological Signalling Studies (bioss), Albert Ludwigs University Freiburg, D-79104 Freiburg, Germany

Corresponding author

Citation Information: Biological Chemistry. Volume 391, Issue 8, Pages 913–922, ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: 10.1515/bc.2010.097, June 2010

Publication History

Published Online:


Some of the phenotypes of mice deficient for the lysosomal cysteine endopeptidase cathepsin L (Ctsl) are characterized by large dysmorphic vesicles in the cytoplasm. Specifically, the heart (dilative cardiomyopathy), the thyroid (impaired thyroglobulin processing) and keratinocytes (periodic hair loss and epidermal hyperproliferation) are affected. We hypothesized that the formation of aberrant vesicles is owing to defects in macroautophagy. Therefore, primary mouse embryonic fibroblasts (MEF), which were derived from Ctsl -/- animals crossed with mice transgenic for the autophagy marker GFP-LC3, were investigated. Ctsl -/- MEF show increased number and size of vesicular structures belonging to the ‘acidic’ cellular compartment and are also characterized by GFP-LC3. Induction of autophagy by nutrient starvation or rapamycin treatment showed no significant impairment of the initiation of autophagy, the formation of autophagosomes or autophagosome-lysosome fusion in Ctsl -/- MEF, but co-localization of GFP-LC3 and Lamp1 revealed unusually large autophagolysosomes filled with Lamp1. Furthermore, the soluble lysosomal enzyme cathepsin D was elevated in Ctsl -/- MEF. Thus, degradation of autophagolysosomal content is impaired in the absence of Ctsl. This could slow the turnover of autophagolysosomes and result in accumulation of the dysmorphic and ‘acidic’ vesicles that were previously described in the context of the pathological phenotypes of Ctsl -/- mice.

Keywords: autophagy; protease; protein turnover

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