Impaired turnover of autophagolysosomes in cathepsin L deficiency
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Julia Dennemärker
Abstract
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.
©2010 by Walter de Gruyter Berlin New York
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- Highlight: 6th General Meeting of the International Proteolysis Society
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- Is BACE1 a suitable therapeutic target for the treatment of Alzheimer's disease? Current strategies and future directions
- Pharmacogenetic features of cathepsin B inhibitors that improve memory deficit and reduce β-amyloid related to Alzheimer's disease
- Proteases in lymphocyte killer function: redundancy, polymorphism and questions remaining
- Pseudo-active sites of protease domains: HGF/Met and Sonic hedgehog signaling in cancer
- Proteolysis of platelet receptors in humans and other species
- Blunting the knife: development of vaccines targeting digestive proteases of blood-feeding helminth parasites
- Impaired turnover of autophagolysosomes in cathepsin L deficiency
- Nuclear cysteine cathepsin variants in thyroid carcinoma cells
- Deletion of cathepsin H perturbs angiogenic switching, vascularization and growth of tumors in a mouse model of pancreatic islet cell cancer
- Cathepsin E enhances anticancer activity of doxorubicin on human prostate cancer cells showing resistance to TRAIL-mediated apoptosis
- Hydrophilic residues surrounding the S1 and S2 pockets contribute to dimerisation and catalysis in human dipeptidyl peptidase 8 (DP8)
- Molecular contortionism – on the physical limits of serpin ‘loop-sheet’ polymers
- The substrate specificity profile of human granzyme A
- Use of granzyme B-based fluorescent protein reporters to monitor granzyme distribution and granule integrity in live cells
Articles in the same Issue
- Guest Editorial
- Highlight: The Biology of Proteolytic Systems
- Highlight: 6th General Meeting of the International Proteolysis Society
- Structure, mechanism and inhibition of γ-secretase and presenilin-like proteases
- Is BACE1 a suitable therapeutic target for the treatment of Alzheimer's disease? Current strategies and future directions
- Pharmacogenetic features of cathepsin B inhibitors that improve memory deficit and reduce β-amyloid related to Alzheimer's disease
- Proteases in lymphocyte killer function: redundancy, polymorphism and questions remaining
- Pseudo-active sites of protease domains: HGF/Met and Sonic hedgehog signaling in cancer
- Proteolysis of platelet receptors in humans and other species
- Blunting the knife: development of vaccines targeting digestive proteases of blood-feeding helminth parasites
- Impaired turnover of autophagolysosomes in cathepsin L deficiency
- Nuclear cysteine cathepsin variants in thyroid carcinoma cells
- Deletion of cathepsin H perturbs angiogenic switching, vascularization and growth of tumors in a mouse model of pancreatic islet cell cancer
- Cathepsin E enhances anticancer activity of doxorubicin on human prostate cancer cells showing resistance to TRAIL-mediated apoptosis
- Hydrophilic residues surrounding the S1 and S2 pockets contribute to dimerisation and catalysis in human dipeptidyl peptidase 8 (DP8)
- Molecular contortionism – on the physical limits of serpin ‘loop-sheet’ polymers
- The substrate specificity profile of human granzyme A
- Use of granzyme B-based fluorescent protein reporters to monitor granzyme distribution and granule integrity in live cells
