Sequentially activated death complexes regulate pyroptosis in response to Yersinia blockade of immune signaling

The innate immune system provides protection against bacterial pathogens by initiating conserved cell death responses following the detection of pathogen associated molecular patterns. Pathogenic Yersinia species inject a virulence protein, YopJ, thereby inhibiting host inflammatory gene expression. YopJ activity triggers caspase-8-dependent cell death that mediates the activation of caspase-1 via a poorly defined mechanism that does not require known inflammasome components. Here we demonstrate that caspase-1 activation by caspase-8 requires caspase-8 dimerization, auto processing, and catalytic activity. Intriguingly, caspase-1 catalytic activity is also required for its own processing downstream of caspase-8, indicating that both caspase-8 enzymatic and scaffolding activity mediate caspase-1 activation. Although the inflammasome adaptor protein ASC is dispensable for caspase-1 activation during Yersinia infection, IL-1β maturation and release in the setting of YopJ-induced cell death requires ASC and occurs via NLRP3 activation downstream of caspase-8-dependent Gasdermin D processing. Notably, active caspase-8 and ASC form sequentially and spatially distinct death complexes during infection. Altogether, this work demonstrates that a network of functionally interconnected, but distinct death complexes mediate cell lysis and IL-1β release in response to pathogen blockade of innate immune signaling.