Caspase-8 induces cleavage of gasdermin D to elicit pyroptosis during Yersinia infection

Significance Here we demonstrate that Yersinia YopJ-induced murine macrophage death involves caspase-8–induced cleavage of both gasdermin D (GSDMD) and gasdermin E (GSDME). The ensuing cell death is rapid, morphologically is similar to pyroptosis, and induces IL-1 release. Recently, both GSDMD and GSDME were reported to be critical effectors of caspase-1/11–driven pyroptosis and caspase-3–dependent secondary necrosis, which prompted the redefinition of pyroptosis as cell death-mediated by gasdermin activation. Our work extends these studies and shows that activation of caspase-8 in the context of TAK1 inhibition results in cleavage of both GSDMD and GSDME, leading to pyroptotic-like cell death. Further study will be needed to determine whether caspase-8 cleaves GSDMD directly or via intermediate substrates.