Cysteine Cathepsins Trigger Caspase-dependent Cell Death through Cleavage of Bid and Antiapoptotic Bcl-2 Homologues
Open accessAbstract
As a model for defining the role of lysosomal cathepsins in apoptosis, we characterized the action of the lysosomotropic agent LeuLeuOMe using distinct cellular models. LeuLeuOMe induces lysosomal membrane permeabilization, resulting in release of lysosomal cathepsins that cleave the proapoptotic Bcl-2 family member Bid and degrade the antiapoptotic member Bcl-2, Bcl-xL, or Mcl-1. The papain-like cysteine protease inhibitor E-64d largely prevented apoptosis, Bid cleavage, and Bcl-2/Bcl-xL/Mcl-1 degradation. The pancaspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp(OMe)fluoromethyl ketone failed to prevent Bid cleavage and degradation of anti-apoptotic Bcl-2 homologues but substantially decreased cell death, suggesting that cathepsin-mediated apoptosis in these cellular models mostly follows a caspase-dependent pathway. Moreover, in vitro experiments showed that one or more of the cysteine cathepsins B, L, S, K, and H could cleave Bcl-2, Bcl-xL, Mcl-1, Bak, and BimEL, whereas no Bax cleavage was observed. On the basis of inhibitor studies, we demonstrate that lysosomal disruption triggered by LeuLeuOMe occurs before mitochondrial damage. We propose that degradation of anti-apoptotic Bcl-2 family members by lysosomal cathepsins synergizes with cathepsin-mediated activation of Bid to trigger a mitochondrial pathway to apoptosis. Moreover, XIAP (X-chromosome-linked inhibitor of apoptosis) was also found to be a target of cysteine cathepsins, suggesting that cathepsins can mediate caspase-dependent apoptosis also downstream of mitochondria.
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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 [776]
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- Authors
- Droga-Mazovec, G., Bojič, L., Petelin, A., Ivanova, S., Romih, R., Repnik, U., Salvesen, G. S., Stoka, V., Turk, V., & Turk, B.
- Affiliations
- Jožef Stefan Institute (SI)
- University of Ljubljana (SI)
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Corresponding author
- Turk, Boris
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2008-07
- Volume
- 283
- Issue
- 27
- Pages
- 19140-19150
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2006193439
- Cited by
- 399
- References
- 67
- Citations by year
- 2026: 13 · 2025: 17 · 2024: 21 · 2023: 21 · 2022: 22 · 2021: 22 · 2020: 23 · 2019: 23 · 2018: 26 · 2017: 22 · 2016: 22 · 2015: 20 · 2014: 24 · 2013: 27 · 2012: 26
- FWCI
- 9.59
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- 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 › Cancer Research › Protease and Inhibitor Mechanisms
- Keywords
- cysteine cathepsins, lysosomal cathepsins, apoptosis, Bid cleavage, Bcl-2 family proteins, Bcl-xL, Mcl-1, Bax, BimEL, Bak, lysosomal membrane permeabilization, E64d, XIAP, mitochondrial apoptosis, caspase-dependent cell death, lysosomal disruption
- MeSH terms
- Bcl-2-Like Protein 11, Cathepsins, Humans, Lysosomes, Membrane Proteins, Mitochondria, Protease Inhibitors, Proto-Oncogene Proteins, Apoptosis, Caco-2 Cells, Proto-Oncogene Proteins c-bcl-2, bcl-2 Homologous Antagonist-Killer Protein, Apoptosis Regulatory Proteins, bcl-X Protein, BH3 Interacting Domain Death Agonist Protein, X-Linked Inhibitor of Apoptosis Protein, Myeloid Cell Leukemia Sequence 1 Protein
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