Cathepsin D Triggers Bax Activation, Resulting in Selective Apoptosis-inducing Factor (AIF) Relocation in T Lymphocytes Entering the Early Commitment Phase to Apoptosis
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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.
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Cytosolic cathepsins usually precipitate RCD by proteolytic activation or inactivation of substrates including BID, BAX, anti-apoptotic BCL2 family members, and XIAP, engaging feed-forward amplification involving MOMP and caspases.
“Cytosolic cathepsins usually precipitate RCD by catalyzing the proteolytic activation or inactivation of several substrates, including BID, BAX, anti-apoptotic BCL2 family members, and XIAP [776–778], hence engaging a feed-forward amplification circuitry of the lethal cascade involving MOMP and caspases.”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [777]
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- Authors
- Bidère, N., Lorenzo, H. K., Carmona, S., Laforge, M., Harper, F., Dumont, C., & Senik, A.
- Affiliations
- Inserm (FR)
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Senik, Anna
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2003-08
- Volume
- 278
- Issue
- 33
- Pages
- 31401-31411
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1984145308
- Cited by
- 435
- References
- 50
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 6 · 2023: 7 · 2022: 12 · 2021: 6 · 2020: 13 · 2019: 7 · 2018: 11 · 2017: 13 · 2016: 13 · 2015: 20 · 2014: 15 · 2013: 25 · 2012: 22
- FWCI
- 13.16
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- cathepsin D, Bax activation, apoptosis-inducing factor, T cells, caspase-independent apoptosis, mitochondrial outer membrane permeabilization, lysosomal destabilization, pepstatin A, staurosporine, vacuolar H+-ATPase, chromatin condensation
- MeSH terms
- Anti-Bacterial Agents, Carrier Proteins, Cathepsin B, Cathepsin D, Cathepsins, Cells, Cultured, Cysteine Endopeptidases, Cytosol, Enzyme Inhibitors, Flavoproteins, Humans, Hydrogen-Ion Concentration, Lysosomes, Membrane Proteins, Mitochondria, Pepstatins, Phenotype, Protease Inhibitors, Proto-Oncogene Proteins, T-Lymphocytes, Signal Transduction, Down-Regulation, Apoptosis, Macrolides, Proto-Oncogene Proteins c-bcl-2, Staurosporine, RNA, Small Interfering, BH3 Interacting Domain Death Agonist Protein, bcl-2-Associated X Protein, Apoptosis Inducing Factor, Cathepsin L
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