Recent Insights into the Molecular Mechanisms Underlying Pyroptosis and Gasdermin Family Functions

GSDMD pore formation leads to pyroptosis upon LPS activation of caspase-11. GSDM N-terminal domains have cytotoxic activity, likely due to pore formation (three confirmed cases so far). GSDM C-terminal domains are autoinhibitory and protect against this cytotoxicity. GSDM family proteins have a role in the regulation of cellular differentiation, likely through programmed cell death, but the mechanisms involved in the activation of other family members remain unclear. Pyroptosis is an inflammatory form of cell death that not only protects multicellular organisms from invading pathogenic bacteria and microbial infections, but can also lead to sepsis and lethal septic shock if overactivated. Here, we present an overview of recent developments within the pyroptosis field, beginning with the discovery of Gasdermin D (GSDMD) as a substrate of caspase-1 and caspase-11 upon detection of cytosolic lipopolysaccharide (LPS). Cleavage releases the N-terminal domain of GSDMD, causing it to form cytotoxic pores in the plasma membrane of cells. We further discuss the implications for the rest of the gasdermin (GSDM) family, which are emerging as mediators of programmed cell death in a variety of processes that regulate cellular differentiation and proliferation. Pyroptosis is an inflammatory form of cell death that not only protects multicellular organisms from invading pathogenic bacteria and microbial infections, but can also lead to sepsis and lethal septic shock if overactivated. Here, we present an overview of recent developments within the pyroptosis field, beginning with the discovery of Gasdermin D (GSDMD) as a substrate of caspase-1 and caspase-11 upon detection of cytosolic lipopolysaccharide (LPS). Cleavage releases the N-terminal domain of GSDMD, causing it to form cytotoxic pores in the plasma membrane of cells. We further discuss the implications for the rest of the gasdermin (GSDM) family, which are emerging as mediators of programmed cell death in a variety of processes that regulate cellular differentiation and proliferation.