Inflammatory caspases (1/4/5) are key effectors in the process of pyroptosis by cleaving and activating the pore-forming protein gasdermin D (GSDMD). Unlike other caspases whose substrates have been well characterized, the substrates for caspase-4, which mediate non-canonical pyroptosis, remain poorly understood. Here, we combined non-canonical amino acids, photo-crosslinking, and proteomics to profile caspase-4 substrates, enabling the capture of transient protein interactions with activated caspase-4. A set of new substrates were identified by photo-crosslinking mass spectrometry, revealing the signaling pathway and biological process affected by pyroptosis. Notably, we found that AKT1 is cleaved at D108, which removes its autoinhibition and membrane localization domain, resulting in the release of activated AKT1. Our results also showed the precursor of caspase-5/12 could be cleaved by caspase-4 to form the p20/p10 active conformation, uncovering a previously unrecognized pyroptotic caspase cascade. Overall, this study presents an approach for identifying caspase-4 substrates and offers further understanding of non-canonical pyroptosis.
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