Lysosomal membrane permeabilization and cathepsin release is a Bax/Bak-dependent, amplifying event of apoptosis in fibroblasts and monocytes
Open accessAbstract
Apoptotic stimuli have been shown to trigger lysosomal membrane permeability (LMP), leading to the release of cathepsins, which activate death signaling pathways in the cytosol. However, it is unknown whether this process is an initiating or amplifying event in apoptosis. In this study, we used fibroblasts and monocytes exposed to etoposide, ultraviolet light, FasL or deprived of interleukin-3 (IL-3) to show that LMP and the cytosolic release of cathepsins B, L and D consistently depends on Bax/Bak and components of the apoptosome. Neither Bax nor Bak resided on the lysosomes, indicating that lysosomes were not directly perforated by Bax/Bak but by effectors downstream of the apoptosome. Detailed kinetic analysis of cells lacking cathepsin B or L or treated with the cysteine protease inhibitor, E64d, revealed a delay in these cells in etoposide- and IL-3 deprivation-induced caspase-3 activation and apoptosis induction but not clonogenic survival, indicating that cathepsins amplify rather than initiate apoptosis.
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- Authors
- Oberle, C., Huai, J., Reinheckel, T., Tacke, M., Rassner, M., Ekert, P. G., Buellesbach, J., & Borner, C.
- Affiliations
- University of Freiburg (DE)
- Royal Children's Hospital (AU)
- Corresponding author
- Borner, C
- Venue
- Cell Death & Differentiation
- Published
- 2010-01-22
- Volume
- 17
- Issue
- 7
- Pages
- 1167-1178
- ISSN
- 1350-9047 (ISSN-L)
- 1476-5403
- OpenAlex
- W2056182070
- Cited by
- 193
- References
- 48
- Citations by year
- 2026: 13 · 2025: 15 · 2024: 12 · 2023: 10 · 2022: 16 · 2021: 16 · 2020: 6 · 2019: 4 · 2018: 16 · 2017: 13 · 2016: 14 · 2015: 15 · 2014: 6 · 2013: 9 · 2012: 13
- FWCI
- 4.82
- Type
- journal article
- Language
- en
- Open access
- green
- hal.science
- Licence
- other-oa
- www.springer.com/tdm (tdm)
- Locations
- Cell Death and Differentiation (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- Trinity's Access to Research Output (TARA) (Trinity College Dublin) (submittedVersion)
- Funders
- Yale University
- European Commission (201279)
- Deutsche Forschungsgemeinschaft (BO-1933, GSC‐4, (EXC 294))
- Deutsche Krebshilfe
- Medical Research Council
- National Health and Medical Research Council
- 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 › Physiology › Calcium signaling and nucleotide metabolism
- Keywords
- lysosomal membrane permeabilization, Bax, Bak, apoptosome, cathepsin B, cathepsin L, cathepsin D, caspase-3 activation, etoposide, Fas ligand, ultraviolet radiation, fibroblasts, monocytes, E64d
- MeSH terms
- Animals, Antineoplastic Agents, Phytogenic, Cathepsins, Cell Membrane Permeability, Etoposide, Fibroblasts, Interleukin-3, Leucine, Lysosomes, Monocytes, Ultraviolet Rays, Cysteine Proteinase Inhibitors, Apoptosis, bcl-2 Homologous Antagonist-Killer Protein, bcl-2-Associated X Protein, Mice, Caspase 3, Fas Ligand Protein, Apoptosomes, Gene Knockdown Techniques
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