Pore-forming activity and structural autoinhibition of the gasdermin family

  title={Pore-forming activity and structural autoinhibition of the gasdermin family},
  author={Jingjin Ding and Kun Wang and Wang Liu and Yang She and Qi Sun and Jianjin Shi and Hanzi Sun and Dacheng Wang and Feng Shao},
Inflammatory caspases cleave the gasdermin D (GSDMD) protein to trigger pyroptosis, a lytic form of cell death that is crucial for immune defences and diseases. GSDMD contains a functionally important gasdermin-N domain that is shared in the gasdermin family. The functional mechanism of action of gasdermin proteins is unknown. Here we show that the gasdermin-N domains of the gasdermin proteins GSDMD, GSDMA3 and GSDMA can bind membrane lipids, phosphoinositides and cardiolipin, and exhibit… 

Structural Insight of Gasdermin Family Driving Pyroptotic Cell Death.

  • J. Ruan
  • Biology
    Advances in experimental medicine and biology
  • 2019
This chapter reviews the current understanding of GSDM proteins in physiological and pathological cell death, with more focused discussions on its structural basis for G SDM activation and pore formation.

The gasdermins, a protein family executing cell death and inflammation

This Review provides a comprehensive overview of the gasdermin family, the mechanisms that control their activation and their role in inflammatory disorders and cancer.

Gasdermins in Innate Host Defense Against Entamoeba histolytica and Other Protozoan Parasites

This work reviews the comprehensive and current knowledge on the expression, activation, biological functions, and regulation of GSDMD cleavage with emphases on physiological scenario and related dysfunctions of each GSDM member as executioner of cell death, cytokine secretion and inflammation against Eh and other protozoan parasitic infections.


Current studies have found that, except for PJVK, the N-terminal domains of almost all GSDMs have the ability to form pores in the plasma membrane, and only the mechanism of GSDMD-induced pyroptosis is relatively clear.

‘Hints' in the killer protein gasdermin D: unveiling the secrets of gasdermins driving cell death

Pyroptosis is a lytic form of cell death distinguished from apoptosis, ferroptosis, necrosis, necroptosis, NETosis, oncosis, pyronecrosis and autophagy. Proinflammatory caspases cleave a gasdermin D

Chemical disruption of the pyroptotic pore-forming protein gasdermin D inhibits inflammatory cell death and sepsis

Pharmacologic inhibition of pyroptotic cell death by necrosulfonamide is efficacious in sepsis models and suggests that gasdermin D inhibitors may be efficacious clinically in inflammatory diseases.

Insights into Gasdermin D activation from the crystal structure of its C-terminal domain

Variations in two additional surface patches involved in interdomain interactions in full-length gasdermins suggest a role of these regions in modulating activation pathways, in agreement with biochemical characterization of different gasdermin proteins.

GSDMD membrane pore formation constitutes the mechanism of pyroptotic cell death

Overall, these data demonstrate that GSDMD is the direct and final executor of pyroptotic cell death.



Activation of the pseudokinase MLKL unleashes the four-helix bundle domain to induce membrane localization and necroptotic cell death

It is shown that the MLKL pseudokinase domain acts as a latch to restrain the N-terminal four-helix bundle (4HB) domain and that unleashing this domain results in formation of a high-molecular-weight, membrane-localized complex and cell death.

Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling

It is shown that gasdermin D is essential for caspase-11-dependent pyroptosis and interleukin-1β maturation and a key mediator of the host response against Gram-negative bacteria.

Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death

Gasdermin D (Gsdmd) is identified by genome-wide clustered regularly interspaced palindromic repeat-Cas9 nuclease screens of caspase-11- and caspasing-1-mediated pyroptosis in mouse bone marrow macrophages to offer insight into inflammasome-mediated immunity/diseases and change the understanding of pyroPTosis and programmed necrosis.

Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis

It is found that the membrane localization of MLKL is essential for Ca2+ influx, which is an early event of TNF-induced necroptosis, and it is identified that TRPM7 (transient receptor potential melastatin related 7) is aMLKL downstream target for the mediation of Ca2- influx and TNF, respectively.

The mechanism of pore assembly for a cholesterol-dependent cytolysin: formation of a large prepore complex precedes the insertion of the transmembrane beta-hairpins.

The hypothesis that PFO forms a large oligomeric prepore complex on the membrane surface prior to the insertion of its transmembrane beta-sheet is strongly supported.

The NLRC4 inflammasome receptors for bacterial flagellin and type III secretion apparatus

It is shown that NAIP5, a BIR-domain NLR protein required for Legionella pneumophila replication in mouse macrophages, is a universal component of the flagellin–NLRC4 pathway and predicts that the remaining NAIP family members may recognize other unidentified microbial products to activate NLRC4 inflammasome-mediated innate immunity.