Gasdermin-Mediated Cell Death Mechanisms

Gasdermins comprise a family of pore-forming proteins that execute lytic forms of programmed cell death, most notably pyroptosis. Under homeostatic conditions, gasdermin N-terminal domains are held inactive by their C-terminal regulators. Activation of inflammatory caspases or other proteases cleaves the interdomain linker, liberating the cytotoxic N-terminus to insert into lipid bilayers and oligomerise into transmembrane pores. These pores dissipate ionic gradients, promote osmotic swelling and trigger plasma membrane rupture, culminating in the release of intracellular contents that act as danger signals. Beyond pyroptosis, gasdermins have been implicated in diverse settings—from innate defence against pathogens to modulation of tumour immunity and neuroinflammation. Emerging evidence reveals that membrane repair mechanisms, accessory proteins such as ninjurin-1, and post-translational modifications of gasdermins finely tune the extent and outcome of cell lysis. By bridging molecular structure with physiological consequence, current research highlights gasdermins as both vital executors of inflammatory death and attractive targets for therapeutic intervention in infections, autoimmunity, stroke and cancer.

Research from Nature Portfolio

Recent structural studies have resolved the architecture of ninjurin-1 assemblies that actively rupture the plasma membrane at the terminal stage of lytic death. High-resolution microscopy and cryo-electron microscopy reveal that ninjurin-1 protomers form amphipathic filaments with distinct hydrophilic and hydrophobic faces, capable of capping membrane edges and driving membrane collapse in concert with gasdermin pores. In parallel, work to enhance tumour cell pyroptosis has demonstrated that blocking ESCRT-III-mediated membrane repair via a nanoparticle-delivered calcium chelator markedly amplifies gasdermin-D-induced pore accumulation. Combined delivery of a bacteria-based gasdermin activator and sustained calcium chelation from injectable hydrogels provokes robust tumour cell lysis, releases pro-inflammatory cytokines and amplifies anti-tumour immunity in primary and metastatic models. Complementing these mechanistic insights, investigation of HMGB1 export shows that this alarmin is not secreted via gasdermin pores under sublytic conditions but is released only upon full membrane rupture, distinguishing mechanisms of cytokine secretion from those of lytic alarmin release in vivo.

Gasdermin-Mediated Cell Death Mechanisms publication trend

The graph below shows the total number of articles in gasdermin-mediated cell death mechanisms across all publications each year (not limited to Nature Index journals).

Technical terms

Gasdermin: A family of proteins whose N-terminal domains form membrane pores following proteolytic cleavage, driving inflammatory cell death.

Pyroptosis: A form of programmed necrotic cell death characterised by gasdermin pore formation, cell swelling and release of pro-inflammatory intracellular contents.

Inflammasome: A multiprotein complex that activates inflammatory caspases in response to cytosolic danger signals, leading to cytokine maturation and gasdermin cleavage.

Pore formation: The oligomerisation of gasdermin N-terminal fragments into ring-shaped structures that perforate cellular membranes, disrupting homeostasis and enabling lytic cell death.

References

1. Structural basis of NINJ1-mediated plasma membrane rupture in cell death. Nature (2023).
2. Enhancing Gasdermin-induced tumor pyroptosis through preventing ESCRT-dependent cell membrane repair augments antitumor immune response. Nature Communications (2022).
3. Indirect regulation of HMGB1 release by gasdermin D. Nature Communications (2020).
4. The Regulation and Modification of GSDMD Signaling in Diseases. Frontiers in Immunology (2022).
5. Caspase-1 and Gasdermin D Afford the Optimal Targets with Distinct Switching Strategies in NLRP1b Inflammasome-Induced Cell Death. Research (2022).
6. Mechanism of membrane pore formation by human gasdermin‐D. The EMBO Journal (2018).