Cathepsin D triggers Bax activation, resulting in selective apoptosis-inducing factor (AIF) relocation in T lymphocytes entering the early commitment phase to apoptosis
| Autor: | Sylvie Carmona, Nicolas Bidère, Mireille Laforge, Anna Senik, Céline Dumont, Hans Kristian Lorenzo, Francis Harper |
|---|---|
| Přispěvatelé: | INSERM U542, Hôpital Paul Brousse |
| Rok vydání: | 2003 |
| Předmět: |
[SDV]Life Sciences [q-bio]
Cathepsin L T-Lymphocytes Cathepsin D Apoptosis Mitochondrion Biochemistry Cathepsin B 0302 clinical medicine Cytosol Pepstatins Staurosporine Enzyme Inhibitors RNA Small Interfering ComputingMilieux_MISCELLANEOUS Cells Cultured bcl-2-Associated X Protein 0303 health sciences Apoptosis Inducing Factor Hydrogen-Ion Concentration Cell biology Anti-Bacterial Agents Mitochondria Cysteine Endopeptidases Phenotype Proto-Oncogene Proteins c-bcl-2 030220 oncology & carcinogenesis Apoptosis-inducing factor Macrolides Intermembrane space medicine.drug BH3 Interacting Domain Death Agonist Protein Signal Transduction Programmed cell death Down-Regulation Biology 03 medical and health sciences Proto-Oncogene Proteins medicine Humans Protease Inhibitors Molecular Biology 030304 developmental biology Cathepsin Flavoproteins Membrane Proteins Cell Biology Cathepsins Carrier Proteins Lysosomes |
| Zdroj: | Journal of Biological Chemistry Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 2003, 278 (33), pp.31401-31411. ⟨10.1074/jbc.M301911200⟩ |
| ISSN: | 0021-9258 1083-351X |
| DOI: | 10.1074/jbc.M301911200⟩ |
| Popis: | Activated human T lymphocytes exposed to apoptotic stimuli targeting mitochondria (i.e. staurosporine), enter an early, caspase-independent phase of commitment to apoptosis characterized by cell shrinkage and peripheral chromatin condensation. We show that during this phase, AIF is selectively released from the intermembrane space of mitochondria, and that Bax undergo conformational change, relocation to mitochondria, and insertion into the outer mitochondrial membrane, in a Bid-independent manner. We analyzed the subcellular distribution of cathepsins (Cat) B, D, and L, in a search for caspase-independent factors responsible for Bax activation and AIF release. All were translocated from lysosomes to the cytosol, in correlation with limited destabilization of the lysosomes and release of lysosomal molecules in a size selective manner. However, only inhibition of Cat D activity by pepstatin A inhibited the early apoptotic events and delayed cell death, even in the presence of bafilomycin A1, an inhibitor of vacuolar type H+-ATPase, which inhibits acidification in lysosomes. Small interfering RNA-mediated gene silencing was used to inactivate Cat D, Bax, and AIF gene expression. This allowed us to define a novel sequence of events in which Cat D triggers Bax activation, Bax induces the selective release of mitochondrial AIF, and the latter is responsible for the early apoptotic phenotype. |
| Databáze: | OpenAIRE |
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