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Updated: May 5, 2026
Exploring Caspase Mutations and Post-Translational Modification by Molecular Modeling Approaches
Published on: October 13, 2022
Caspase-2 promotes cytoskeleton protein degradation during apoptotic cell death
H Vakifahmetoglu-Norberg1, E Norberg, A B Perdomo
1Division of Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm 171 77, Sweden.
Abstract:
The caspase family of proteases cleaves large number of proteins resulting in major morphological and biochemical changes during apoptosis. Yet, only a few of these proteins have been reported to selectively cleaved by caspase-2. Numerous observations link caspase-2 to the disruption of the cytoskeleton, although it remains elusive whether any of the cytoskeleton proteins serve as bona fide substrates for caspase-2. Here, we undertook an unbiased proteomic approach to address this question. By differential proteome analysis using two-dimensional gel electrophoresis, we identified four cytoskeleton proteins that were degraded upon treatment with active recombinant caspase-2 in vitro. These proteins were degraded in a caspase-2-dependent manner during apoptosis induced by DNA damage, cytoskeleton disruption or endoplasmic reticulum stress. Hence, degradation of these cytoskeleton proteins was blunted by siRNA targeting of caspase-2 and when caspase-2 activity was pharmacologically inhibited. However, none of these proteins was cleaved directly by caspase-2. Instead, we provide evidence that in cells exposed to apoptotic stimuli, caspase-2 probed these proteins for proteasomal degradation. Taken together, our results depict a new role for caspase-2 in the regulation of the level of cytoskeleton proteins during apoptosis.
Insights
Caspase-2 does not directly cleave cytoskeleton proteins during apoptosis. Instead, it targets them for proteasomal degradation, revealing a new regulatory role in apoptosis.
Area of Science:
- Cell Biology
- Biochemistry
- Molecular Biology
Background:
- Apoptosis involves caspase proteases that cleave cellular proteins, causing morphological and biochemical changes.
- Caspase-2's role in apoptosis is linked to cytoskeleton disruption, but its direct substrates remain largely unknown.
Purpose of the Study:
- To identify cytoskeleton proteins degraded during apoptosis.
- To investigate whether caspase-2 directly cleaves these proteins or influences their degradation.
Main Methods:
- Unbiased proteomic analysis using two-dimensional gel electrophoresis.
- Differential proteome analysis of cells treated with active recombinant caspase-2.
- Assessment of protein degradation during apoptosis induced by various stressors.
- Validation using siRNA targeting caspase-2 and pharmacological inhibition of caspase-2 activity.
Main Results:
- Four cytoskeleton proteins were identified as degraded upon treatment with active caspase-2.
- These proteins were degraded in a caspase-2-dependent manner during apoptosis.
- No direct cleavage of these cytoskeleton proteins by caspase-2 was observed.
- Evidence suggests caspase-2 targets these proteins for proteasomal degradation during apoptosis.
Conclusions:
- Caspase-2 plays a novel role in regulating cytoskeleton protein levels during apoptosis.
- This regulation occurs via the proteasomal degradation pathway, not direct cleavage.
- The findings provide new insights into the mechanisms of apoptosis and caspase-2 function.
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