AI Article Synopsis
- Activation of procaspase-8 in the death-inducing signaling complex (DISC) is essential for initiating apoptosis, a process of programmed cell death.
- Researchers created a cell-penetrating peptide, DEDid, to mimic a specific region of procaspase-8, and made mutations to interfere with its type I interactions.
- Blocking these interactions led to reduced assembly of the DISC, decreased caspase activation, and inhibited apoptosis, suggesting potential strategies for targeting DED proteins in diseases linked to cell death and inflammation.
Article Abstract
Activation of procaspase-8 in the death effector domain (DED) filaments of the death-inducing signaling complex (DISC) is a key step in apoptosis. In this study, a rationally designed cell-penetrating peptide, DEDid, was engineered to mimic the h2b helical region of procaspase-8-DED2 containing a highly conservative FL motif. Furthermore, mutations were introduced into the DEDid binding site of the procaspase-8 type I interface. Additionally, our data suggest that DEDid targets other type I DED interactions such as those of FADD. Both approaches of blocking type I DED interactions inhibited CD95L-induced DISC assembly, caspase activation and apoptosis. We showed that inhibition of procaspase-8 type I interactions by mutations not only diminished procaspase-8 recruitment to the DISC but also destabilized the FADD core of DED filaments. Taken together, this study offers insights to develop strategies to target DED proteins, which may be considered in diseases associated with cell death and inflammation.
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| http://dx.doi.org/10.1016/j.chembiol.2024.06.014 | DOI Listing |
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