Caspase-8 induces cleavage of gasdermin D to elicit pyroptosis during <i>Yersinia</i> infection

TLDR

Recent work has shown that gasdermin D and E are key mediators of pyroptosis and secondary necrosis, redefining pyroptosis as gasdermin‑driven cell death. The study aims to determine whether caspase‑8 directly cleaves gasdermin D or acts through intermediate substrates. Yersinia YopJ‑induced macrophage death is mediated by caspase‑8–dependent cleavage of gasdermin D and E, producing rapid pyroptosis‑like cell death with IL‑1 release, and this effect is triggered by TAK1 inhibition.

Abstract

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.