Extended Data Fig. 17: Model for membrane repair driven by caspase-7.

a, IECs detect the activity of the Salmonella T3SS via NLRC4 and activate caspase-1 in response. Caspase-1 then activates both the gasdermin D pore as well as caspase-7. We propose a model in which caspase-7 diffuses through the gasdermin D pore, thereby entering the extracellular space. Simultaneously, the gasdermin D pore triggers lysosomal exocytosis, thus delivering ASM to the extracellular space. In this model, caspase-7 and ASM meet in the extracellular space. Note that additional studies will be needed to validate the location of the caspase-7 and ASM interaction. Caspase-7 cleaves ASM, increasing its enzymatic activity and generating more ceramide. This ceramide can then be used for continuous endocytic repair of gasdermin D pores to facilitate IEC extrusion. b, NK cells or CTLs attack by degranulating perforin and granzyme B. Perforin pores allow granzyme B to enter the target cell, where it activates caspase-3 (not shown) and caspase-7. Activated caspase-7 can exit the cell to encounter ASM, which generates ceramide that should allow endocytosis of perforin pores. We propose that this maintains cell integrity long enough for the cell to complete caspase-3-driven apoptosis.