Authors
Grant, S., Nicholson, E., Chen, Z. H. X., Robson, C., Viswanathan, B., Chang, Y., Sung, A. W., Patel, P., Kleppen, J., Ozdenya, T., Chen, K., Spicer, C. D., Boucher, D.
Abstract
The coordination of efficient immune responses to infections is essential to enable pathogen clearance and host survival. Cell death modalities are a crucial component of the innate immune system and are key to controlling intracellular and extracellular infections. Human caspase-4 and -5 are cysteine proteases activated upon intracellular detection of bacterial lipopolysaccharide (LPS) and triggers pyroptosis, a lytic and pro-inflammatory form of cell death. However, the interaction between these caspases and other cell death modalities remains poorly understood. Here, we build on evidence that caspase-4 can engage in crosstalk with the apoptotic executioner caspases-3 and -7. Our work validated caspase-3 and -7 as direct substrates of caspase-4 and -5, and demonstrated that this specificity was regulated by exosite interactions as opposed to the tetrapeptide. Using AlphaFold, we generated an interaction model between caspase-4 and executioner caspases-3 and -7. From this, we experimentally validated the importance of a hydrophobic interface on caspase-3 and -7 that engaged the caspase-4 exosite, enabling their recognition and cleavage. Importantly, this interface is not used by the apoptotic initiator caspase-8, which cleaved caspase-3 in a tetrapeptide-dependent manner. Our work highlights that inflammatory caspases have evolved a novel mechanism to coordinate crosstalk between pyroptotic and apoptotic signalling, and suggests that these pathways may synergise for the efficient amplification of cell death pathways.
Preprint server:
bioRxiv
The authors list and abstract were imported from bioRxiv on 03 Nov 2025.
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