Partners with a killer: Metabolic signaling promotes inflammatory cell death

Abstract

In this issue of Cell, Evavold et al. (2021) report that mTOR Complex 1 (mTORC1), a metabolic signaling complex, controls reactive oxygen species (ROS) production in mitochondria, which in turn promotes inflammatory cell death mediated by gasdermin D (GSDMD). This provides a new mechanistic connection between metabolic signaling and inflammatory cell death.

Figure 1.. The Ragulator-Rag-mTORC1 pathway promotes GSDMD oligomerization and pore formation

Upon inflammasome stimulation, activated inflammatory caspases process GSDMD into NT-GSDMD and CT-GSDMD. NT-GSDMD translocates to plasma membrane and oligomerizes to form pores that mediate cytokine secretion and pyroptotic cell death. The Ragulator-Rag-mTORC1 pathway at the lysosomal membrane regulates ROS production in mitochondria that promotes the oligomerization and pore formation by NT-GSDMD. Deficiency or inhibition of Rag proteins or mTORC1 components diminishes NT-GSDMD-mediated pore formation and cytolysis. The Ragulator-Rag complex also regulates pyroptosis upstream of GSDMD cleavage through caspase-8 activation.