The pore-forming protein gasdermin D is a cellular redox sensor

Reactive oxygen species (ROS) affect inflammation and immunity in a multitude of ways, in particular in the context of the signaling pathways that determine cell fate. Inflammasomes are multiprotein cytoplasmic complexes whose pyroptosis-inducing activities are controlled by ROS. Our knowledge of how ROS mediates inflammasome activities is largely based on studies of the initiating events in these pathways. Herein, we show that ROS controls the terminal events in the pyroptosis pathways. We found that ROS oxidizes the protein gasdermin D (GSDMD) and promotes its assembly into a death-inducing pore forming complex. Mechanistically, ROS enhances GSDMD-mediated pyroptosis in an intrinsic manner, likely through oxidative modification of a specific cysteine residue (C192). Diverse ROS sources promote GSDMD oxidation, ranging from homeostatic control via the Ragulator-Rag complex, to inducible control via diverse microbial products and environmental toxins. These findings expand the steps in the inflammasome pathway that are controlled by ROS and suggest that GSDMD operates as a pyroptosis-inducing redox sensor. ### Competing Interest Statement J.C.K. consults for IFM Therapeutics and consults and holds equity in Corner Therapeutics, Larkspur Biosciences and Neumora Therapeutics. None of these relationships influenced the work performed in this study. The other authors declare that they have no competing interests.