Gasdermin D activity in inflammation and host defense

The mechanisms underlying the release of interleukin-1 (IL-1) family cytokines from phagocytes have been the subject of intense investigations for more than 30 years. The absence of an amino-terminal secretion signal from members of this family suggests a previously unknown mechanism of protein secretion that transfers cytosolic IL-1 directly across the plasma membrane into the extracellular space. The pore-forming protein gasdermin D (GSDMD) has emerged as the conduit for IL-1 secretion from the cytosol, serving to induce the release of IL-1 from living (hyperactive) or dead (pyroptotic) cells. In this Review, we discuss the mechanism by which GSDMD pore formation is regulated by the activity of inflammatory caspases, which are commonly associated with inflammasomes. We discuss how GSDMD promotes IL-1 release from hyperactive or pyroptotic cells, with a specific focus on defining how these distinct cell fates associated with GSDMD activity can be regulated. Last, the physiological consequences of GSDMD activity and therapeutic potential of targeting this pore-forming protein are discussed, which highlight the abundance of questions that remain to be answered by the community.