Beyond inflammasomes: emerging function of gasdermins during apoptosis and NETosis

Abstract

Programmed cell death is a key mechanism involved in several biological processes ranging from development and homeostasis to immunity, where it promotes the removal of stressed, damaged, malignant or infected cells. Abnormalities in the pathways leading to initiation of cell death or removal of dead cells are consequently associated with a range of human diseases including infections, autoinflammatory disease, neurodegenerative disease and cancer. Apoptosis, pyroptosis and NETosis are three well-studied modes of cell death that were traditionally believed to be independent of one another, but emerging evidence indicates that there is extensive cross-talk between them, and that all three pathways can converge onto the activation of the same cell death effector-the pore-forming protein Gasdermin D (GSDMD). In this review, we highlight recent advances in gasdermin research, with a particular focus on the role of gasdermins in pyroptosis, NETosis and apoptosis, as well as cell type-specific consequences of gasdermin activation. In addition, we discuss controversies surrounding a related gasdermin family protein, Gasdermin E (GSDME), in mediating pyroptosis and secondary necrosis following apoptosis, chemotherapy and inflammasome activation.Pore-forming activity and structural autoinhibition of the gasdermin family. Nature 535: 111 -116

Hypoxia-preconditioned olfactory mucosa mesenchymal stem cells abolish cerebral ischemia/reperfusion-induced pyroptosis and apoptotic death of microglial cells by activating HIF-1α

“…Induction of the inflammasome complex activates caspase-1 and facilitates formation of GSDMD, which further promotes secretion of pro-inflammation cytokines IL-1β and IL-18 from the pore of the cell membrane resulting in inflammation-associated pyroptotic cell death [5,35]. It has been reported that activation of inflammasome induces apoptosis [36]. Apoptosis is a highly mediated subtype of cell death, which is particularly linked to the cerebral reperfusion phase.…”

Netosis and Inflammasomes in Large Vessel Occlusion Thrombi

“…Inflammasomes process the pro-inflammatory cytokines IL-1β and IL-18 into their active forms ( de Rivero Vaccari et al, 2014 ; de Rivero Vaccari et al, 2016 ). In neutrophils, activated caspase-1 or caspase-11 cleave gasdermin-D (GSDM-D), which leads to pyroptosis and NETosis ( Chen et al, 2018 ; Chen et al, 2020 ). Moreover, NETs are downstream of neutrophil inflammasome activation ( Chen et al, 2018 ; Sollberger et al, 2018 ; Westerterp et al, 2018 ).…”

Caspase-8–dependent gasdermin D cleavage promotes antimicrobial defense but confers susceptibility to TNF-induced lethality

“…Gasdermin D (GSDMD) is a pore-forming protein that has emerged as an important player during different modes of cell death including pyroptosis, apoptosis, and NETosis ( 1 ). GSDMD consists of a cytotoxic N-terminal domain (GSDMD NT ) and a repressor C-terminal domain (GSDMD CT ) that is connected by a flexible linker ( 2 ).…”