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Published on: August 2, 2021
Cathepsin D primes caspase-8 activation by multiple intra-chain proteolysis
Sébastien Conus1, Cristina Pop, Scott J Snipas
1Institute of Pharmacology, University of Bern, CH-3010 Bern, Switzerland. sebastien.conus@pki.unibe.ch
The Journal of Biological Chemistry
|April 25, 2012
Summary
Cathepsin D directly activates caspase-8 through proteolysis and dimerization, initiating the caspase cascade for neutrophil apoptosis. This mechanism, involving specific cleavage and stabilization of caspase-8, is crucial for triggering programmed cell death.
Area of Science:
- Cell Biology
- Molecular Biology
- Immunology
Background:
- Neutrophils undergo apoptosis during inflammatory resolution.
- Caspase-8 activation is critical for initiating neutrophil apoptosis.
- The precise mechanism of caspase-8 activation by cathepsin D remains unclear.
Purpose of the Study:
- To elucidate the mechanism by which cathepsin D activates caspase-8.
- To determine the roles of cathepsin D-mediated proteolysis and caspase-8 homodimerization in activation.
- To investigate if cathepsin D can initiate the caspase cascade.
Main Methods:
- Site-specific mutagenesis of caspase-8.
- In vitro assays using recombinant proteins and inhibitors (pepstatin A).
- Affinity labeling with active site probes.
Main Results:
- Cathepsin D specifically cleaves and activates caspase-8 at acidic pH, requiring both proteolysis and homodimerization.
- Cleavage by cathepsin D stabilizes the active site of caspase-8.
- Pre-cleaved caspase-8 by cathepsin D activates caspase-3 in cell-free assays.
Conclusions:
- Cathepsin D directly initiates the caspase cascade by activating caspase-8.
- This mechanism of caspase-8 activation is essential for neutrophil apoptosis.
- Ubiquitous expression of cathepsin D suggests a general role in apoptosis induction.
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