Journal Club

Transplantation of gasdermin pores by extracellular vesicles propagates pyroptosis to bystander cells

Cell 2024

Highlights

• Intercellular propagation of pyroptosis occurs in vitro and in vivo

• EVs released from pyroptotic cells drive bystander cell death

• DNA-PAINT super-resolution microscopy reveals GSDMD pores on pyroptotic EVs

• Pyroptotic EVs transplant GSDMD pores on bystander cells disseminating pyroptosis

Summary

Pyroptosis mediated by gasdermins (GSDMs) plays crucial roles in infection and inflammation. Pyroptosis triggers the release of inflammatory molecules, including damage-associated molecular patterns (DAMPs). However, the consequences of pyroptosis—especially beyond interleukin (IL)-1 cytokines and DAMPs—that govern inflammation are poorly defined. Here, we show intercellular propagation of pyroptosis from dying cells to bystander cells in vitro and in vivo. We identified extracellular vesicles (EVs) released by pyroptotic cells as the propagator of lytic death to naive cells, promoting inflammation. DNA-PAINT super-resolution and immunoelectron microscopy revealed GSDMD pore structures on EVs released by pyroptotic cells. Importantly, pyroptotic EVs transplant GSDMD pores on the plasma membrane of bystander cells and kill them. Overall, we demonstrate that cell-to-cell vesicular transplantation of GSDMD pores disseminates pyroptosis, revealing a domino-like effect governing disease-associated bystander cell death.