The coordination of efficient immune responses to infection is essential to enable pathogen clearance and host survival. Caspases are a family of cysteine proteases which drive cellular responses by cleaving and activating a defined set of proteins. Different caspases have distinct activation stimuli and substrate repertoire, meaning the response generated is dependent on which caspases are activated in a cell. Human caspase-4 is an inflammatory caspase activated upon intracellular detection of bacterial lipopolysaccharide (LPS), and triggers pro-inflammatory responses via cytokine release, and pyroptotic cell death. Previous literature has also demonstrated the importance of apoptotic executioner caspase-3 in gram-negative bacterial immune responses and has linked its activation to caspase-4, but the molecular basis of how this crosstalk is orchestrated is unknown. Here, we demonatrate that caspase-3 is directly cleaved and activated by caspase-4, and that this specificty is not regulated by traditional active site interactions. Instead, specificity was found to be entirely mediated by an exosite, a molecular interface distal from the caspase-4 active site. Using AlphaFold, we generated an interaction model between caspase-4 and caspases-3, and experimentally validated the importance of a hydrophobic interface on caspase-3 that was engaged by the exosite, enabling its cleavage and activation by caspase-4. Strikingly, this interface is not used other caspases, such as apopotiic initiator caspase-8, which targeted caspase-3 via active-site interactions. Finally, alligntment of residues involved at the exosite interface revealed stronge conservation only within the mammals, suggesting that this may be a recently evolved signalling axis exclusive to this lineage. Together, our work elucidates the molcular underpinnings of a novel signalling axis, which has only recently evolved in the mammlain lineage to enable efficient clearance of intracellular bacterial infections.