| Lysosomal serine protease CLN2 regulates tumor necrosis factor-alpha-mediated apoptosis in a Bid-dependent manner. | |
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MedLine Citation:
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PMID: 19246452 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Apoptosis is a highly organized, energy-dependent program by which multicellular organisms eliminate damaged, superfluous, and potentially harmful cells. Although caspases are the most prominent group of proteases involved in the apoptotic process, the role of lysosomes has only recently been unmasked. This study investigated the role of the lysosomal serine protease CLN2 in apoptosis. We report that cells isolated from patients affected with late infantile neuronal ceroid lipofuscinosis (LINCL) having a deficient activity of CLN2 are resistant to the toxic effect of death ligands such as tumor necrosis factor (TNF), CD95 ligand, or tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) but not to receptor-independent stress agents. CLN2-deficient cells exhibited a defect in TNF-induced Bid cleavage, release of cytochrome c, and caspase-9 and -3 activation. Moreover, extracts from CLN2-overexpressing cells or a CLN2 recombinant protein were able to catalyze the in vitro cleavage of Bid. Noteworthy, correction of the lysosomal enzyme defect of LINCL fibroblasts using a medium enriched in CLN2 protein enabled restoration of TNF-induced Bid and caspase-3 processing and toxicity. Conversely, transfection of CLN2-corrected cells with small interfering RNA targeting Bid abrogated TNF-induced cell death. Altogether, our study demonstrates that genetic deletion of the lysosomal serine protease CLN2 and the subsequent loss of its catalytic function confer resistance to TNF in non-neuronal somatic cells, indicating that CLN2 plays a yet unsuspected role in TNF-induced cell death. |
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Authors:
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Hélène Autefage; Virginie Albinet; Virginie Garcia; Hortense Berges; Marie-Laure Nicolau; Nicole Therville; Marie-Françoise Altié; Catherine Caillaud; Thierry Levade; Nathalie Andrieu-Abadie |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2009-02-26 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 284 ISSN: 0021-9258 ISO Abbreviation: J. Biol. Chem. Publication Date: 2009 Apr |
Date Detail:
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Created Date: 2009-04-20 Completed Date: 2009-06-08 Revised Date: 2010-09-22 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 11507-16 Citation Subset: IM |
Affiliation:
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INSERM U858, 31432 Toulouse, France. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Aminopeptidases Animals Apoptosis* BH3 Interacting Domain Death Agonist Protein / metabolism* CHO Cells Caspase 3 / metabolism Caspase 9 / metabolism Catalysis Cricetinae Cricetulus Cytochromes c / metabolism Dipeptidyl-Peptidases and Tripeptidyl-Peptidases Endopeptidases / metabolism, physiology* Fibroblasts / metabolism Humans Lysosomes / metabolism* Neurons / metabolism Recombinant Proteins / chemistry Serine Proteases Tumor Necrosis Factor-alpha / metabolism* |
| Chemical | |
Reg. No./Substance:
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0/BH3 Interacting Domain Death Agonist Protein; 0/BID protein, human; 0/Recombinant Proteins; 0/Tumor Necrosis Factor-alpha; 9007-43-6/Cytochromes c; EC 3.4.-/Endopeptidases; EC 3.4.-/Serine Proteases; EC 3.4.11.-/Aminopeptidases; EC 3.4.14.-/Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; EC 3.4.14.9/tripeptidyl-peptidase 1; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspase 9 |
| Comments/Corrections | |
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