| RRC ID |
11810
|
| 著者 |
Dennemärker J, Lohmüller T, Müller S, Aguilar SV, Tobin DJ, Peters C, Reinheckel T.
|
| タイトル |
Impaired turnover of autophagolysosomes in cathepsin L deficiency.
|
| ジャーナル |
Biol Chem
|
| 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.
|
| 巻・号 |
391(8)
|
| ページ |
913-22
|
| 公開日 |
2010-8-1
|
| DOI |
10.1515/BC.2010.097
|
| PMID |
20536383
|
| MeSH |
Animals
Autophagy*
Biomarkers / metabolism
Cathepsin D / metabolism
Cathepsin L / genetics
Cathepsin L / physiology*
Cells, Cultured
Embryo, Mammalian
Green Fluorescent Proteins / genetics
Green Fluorescent Proteins / metabolism
Lysosome-Associated Membrane Glycoproteins / metabolism
Lysosomes / metabolism*
Lysosomes / pathology
Mice
Mice, Knockout
Mice, Transgenic
Microscopy, Confocal
Microscopy, Electron, Transmission
Microscopy, Fluorescence
Microtubule-Associated Proteins / genetics
Microtubule-Associated Proteins / metabolism
Organelle Size
Phagosomes / metabolism*
Phagosomes / pathology
Recombinant Fusion Proteins / metabolism
|
| IF |
3.27
|
| 引用数 |
49
|
|
WOS 分野
|
BIOCHEMISTRY & MOLECULAR BIOLOGY
|
| リソース情報 |
| 実験動物マウス |
RBRC00806 |
