Gasdermins: Effectors of Pyroptosis

Caspase-1-programmed cell death observed in 1992 was later termed pyroptosis to differentiate it from the morphologically distinct apoptosis. The pyroptosis effector remained unknown until 2015 when gasdermin D was discovered as a cleavage target for caspase-1 and -11. The N terminus of gasdermin D is a PFD that permeabilizes the plasma membrane, simultaneously releasing mature IL-1β and driving cell swelling until membrane rupture. Membrane rupture disperses soluble cytosolic contents. Organelles and intracellular bacteria remain trapped within the torn but largely intact plasma membrane. This PIT promotes transfer of trapped bacteria to neutrophils. Other gasdermin superfamily proteins have homologous, PFDs. DFNA5, one member of this family, is activated by caspase-3, converting apoptosis into lytic cell death. Pyroptosis is a form of lytic programmed cell death initiated by inflammasomes, which detect cytosolic contamination or perturbation. This drives activation of caspase-1 or caspase-11/4/5, which cleave gasdermin D, separating its N-terminal pore-forming domain (PFD) from the C-terminal repressor domain (RD). The PFD oligomerizes to form large pores in the membrane that drive swelling and membrane rupture. Gasdermin D is one of six (in humans) gasdermin family members; several other gasdermins have also been shown to form pores that cause pyroptosis after cleavage to activate their PFDs. One of these, gasdermin E, is activated by caspase-3 cleavage. We review our current understanding of pyroptosis as well as current knowledge of the gasdermin family. Pyroptosis is a form of lytic programmed cell death initiated by inflammasomes, which detect cytosolic contamination or perturbation. This drives activation of caspase-1 or caspase-11/4/5, which cleave gasdermin D, separating its N-terminal pore-forming domain (PFD) from the C-terminal repressor domain (RD). The PFD oligomerizes to form large pores in the membrane that drive swelling and membrane rupture. Gasdermin D is one of six (in humans) gasdermin family members; several other gasdermins have also been shown to form pores that cause pyroptosis after cleavage to activate their PFDs. One of these, gasdermin E, is activated by caspase-3 cleavage. We review our current understanding of pyroptosis as well as current knowledge of the gasdermin family. phagocytosis or endocytosis of dead cells by another cell. Apoptotic bodies are typically efferocytosed by macrophages, but can also be efferocytosed by stromal cells. We recently proposed to extend the term efferocytosis to include phagocytosis of PITs by neutrophils. a family of protein (6 in humans, 10 in mice) that have a homologous N-terminal gasdermin domain. Upon activation, this domain forms a pore in the plasma membrane (this activity has not been studied for DFNB59 at this time). Gasdermins are activated by proteolytic cleavage between their N-terminal and C-terminal domains. the pore formed by an activated gasdermin PFD, sometimes previously called the pyroptotic pore. a platform that activates caspase-1. The inflammasome includes the sensor protein (NLR, AIM2, Pyrin) that oligomerizes in response to a cytosolic stimulus. In many cases the adaptor protein ASC is also included in the term inflammasome; inflammasomes trigger the polymerization of the entire cellular content of ASC into an ASC speck. Caspase-11 is a noncanonical inflammasome that directly detects cytosolic LPS, functioning in parallel to caspase-1. remnants of a cell after its membrane ruptures as a consequence of swelling due to a membrane pore, including the gasdermin pore that causes pyroptotic membrane rupture. PITs are composed of the ruptured, but otherwise mostly intact plasma membrane that retains (traps) organelles and intracellular bacteria. cell death that occurs because of specific signaling events within a cell. In contrast, non-programmed cell death (necrosis) results from thermal, chemical, or other physical damage. programmed lytic cell death by membrane rupture that is a consequence of a gasdermin pore. Cells with open gasdermin pores theoretically could avert pyroptosis by initiating regulatory volume decrease and repairing their membranes. Typically the gasdermin pore causes swelling, and in short order this results in physical rupture in the plasma membrane that marks the irreversible death of the cell.