Interaction between caspases and their substrates in the inflammasome signaling pathway
2019
Hochschulschrift
Zugriff:
Caspases are a family of cysteine proteases that play an important role in anti-microbial immune responses and inflammatory disorders. They can be divided into several subfamilies, one of which is the inflammatory caspases, including caspases-1, -4, -5 and -11. Inflammatory caspases are activated by the inflammasome signaling pathways. Active caspase-1 is able to convert prointerleukin-1 beta (pro-IL-1 beta to its mature form, which facilitates its secretion. Recent studies identified the gasdermin D (GSDMD) protein as a substrate of caspases-1, -4, -5 and -11 and a mediator of pyroptotic cell death. Both pro-IL1 beta and GSDMD are substrates of caspases downstream of the inflammasome signaling pathway. In this study, I investigated the molecular mechanisms of the interaction between caspases and these two substrates. Caspase inhibitors are useful tools for studying both apoptosis and pyroptosis. Based on our understanding of the mechanisms for caspasegasdermin D recognition, we designed an inhibitor Ac-FLTD-CMK, which is specific for the inflammatory caspases. The inhibitor consists of an FLTD peptide from the GSDMD cleavage site, which is recognizable by inflammatory caspases. The C-terminus of the peptide is modified by a chloromethylketone (CMK) moiety to react with the active site cysteine residue from caspases. Our in vitro caspase inhibition data demonstrates that the Ac-FLTD-CMK inhibitor is of high potency against caspases-1, -4, -5 and -11, but did not inhibit the apoptotic caspase-3. Ac-FLTD-CMK inhibits pyroptosis in both the NLRP3 and non-canonical inflammasome pathways. Crystal structures of caspase-1 and Ac-FLTD-CMK complex revealed the molecular mechanisms of how the inhibitor binds and inhibits inflammatory caspases. Our study sheds light on the mechanisms of GSDMD recognition by caspases and provides a novel tool for investigating inflammasomes and pyroptosis.
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Interaction between caspases and their substrates in the inflammasome signaling pathway
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Autor/in / Beteiligte Person: | Yang, Rui |
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Veröffentlichung: | 2019 |
Medientyp: | Hochschulschrift |
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