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Caspases and their substrates
Open accessAbstract
Protease biology is intimately linked to the functional consequences of substrate cleavage events. Human caspases are a family of 12 fate-determining cysteine proteases that are best known for driving cell death, either apoptosis or pyroptosis. More recently, caspases have been shown to be involved in other cellular remodeling events as well including stem cell fate determination, spermatogenesis, and erythroid differentiation. Recent global proteomics methods enable characterization of the substrates that caspases cleave in live cells and cell extracts. The number of substrate targets identified for individual caspases can vary widely ranging from only a (few) dozen targets for caspases-4, -5, -9, and -14 to hundreds of targets for caspases-1, -2, -3, -6, -7, and -8. Proteomic studies characterizing the rates of target cleavage show that each caspase has a preferred substrate cohort that sometimes overlaps between caspases, but whose rates of cleavage vary over 500-fold within each group. Determining the functional consequences of discrete proteolytic events within the global substrate pool is a major challenge for the field. From the handful of individual targets that have been studied in detail, there are only a few so far that whose single cleavage event is capable of sparking apoptosis alone, such as cleavage of caspase-3/-7 and BIM EL, or for pyroptosis, gasdermin D. For the most part, it appears that cleavage events function cooperatively in the cell death process to generate a proteolytic synthetic lethal outcome. In contrast to apoptosis, far less is known about caspase biology in non-apoptotic cellular processes, such as cellular remodeling, including which caspases are activated, the mechanisms of their activation and deactivation, and the key substrate targets. Here we survey the progress made in global identification of caspase substrates using proteomics and the exciting new avenues these studies have opened for understanding the molecular logic of substrate cleavage in apoptotic and non-apoptotic processes.
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“Activated CASP9 can catalyze the proteolytic activation of CASP3 and CASP7, which are widely perceived as the enzymes responsible for cell demolition during intrinsic (and extrinsic, see below) apoptosis in mammalian cells (and hence are commonly known as executioner caspases) [179, 180].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [179]
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Galluzzi, L., Vitale, I., Aaronson, S. A., Abrams, J. M., Adam, D., Agostinis, P., Alnemri, E. S., Altucci, L., Amelio, I., Andrews, D. W., et al. (2018) · Cell Death & Differentiation · doi:10.1038/s41418-017-0012-4 · Cited by 6,680
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Caspases in Cell Death, Inflammation, and Disease
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BAK/BAX macropores facilitate mitochondrial herniation and mtDNA efflux during apoptosis
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Metadata
- Authors
- Julien, O., & Wells, J. A.
- Affiliations
- University of California, San Francisco (US)
- Corresponding author
- Wells, James A
- Venue
- Cell Death & Differentiation
- Published
- 2017-05-12
- Volume
- 24
- Issue
- 8
- Pages
- 1380-1389
- ISSN
- 1350-9047 (ISSN-L)
- 1476-5403
- PMC
- PMC5520456
- OpenAlex
- W2613163105
- Cited by
- 816
- References
- 102
- Citations by year
- 2026: 61 · 2025: 98 · 2024: 108 · 2023: 94 · 2022: 110 · 2021: 117 · 2020: 89 · 2019: 73 · 2018: 47 · 2017: 19
- FWCI
- 5.79
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Cell Death and Differentiation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of General Medical Sciences (R01GM081051)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- caspases, caspase substrates, substrate cleavage, apoptosis, pyroptosis, cysteine protease, synthetic lethality, gasdermin D, caspase activation, cellular remodeling, stem cell fate determination, spermatogenesis, erythroid differentiation
- MeSH terms
- Pyroptosis, Bcl-2-Like Protein 11, Gasdermins, Animals, Cell Differentiation, Eukaryotic Cells, Gene Expression Regulation, Humans, Kinetics, Neoplasm Proteins, Substrate Specificity, Signal Transduction, Caspases, Phosphate-Binding Proteins, Intracellular Signaling Peptides and Proteins, Proteolysis
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