Cholesterol constrains pore formation by mammalian gasdermins

Pyroptosis, a lytic form of cell death, is executed by gasdermin pores. Researchers conducted a CRISPR screen to identify genes necessary for gasdermin D (GSDMD) pore activity in macrophages. They discovered that the endosome adaptor Rabgef1 acts as a positive regulator of pore formation. When Rabgef1 is deficient, NT-GSDMD can bind to membranes but fails to oligomerize and trigger lytic death.

This deficiency leads to an excess of cholesterol on the plasma membrane. By reducing or redistributing cholesterol through various methods, GSDMD oligomerization and pyroptosis can be restored. The regulation of membrane cholesterol and pore formation by Rabgef1 is a general mechanism for the gasdermin family. In cancer cells, organoids, and tumors, lowering cholesterol sensitizes resistant cells to GSDME pyroptosis induced by synthetic mRNAs, chemogenetic induction, and chemotherapy.

These findings establish cholesterol content as an endogenous checkpoint for gasdermin-mediated pyroptotic cell death during its execution phase, with potential implications for metabolic disease and cancer immunotherapy.