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The gasdermins, a protein family executing cell death and inflammation

Abstract

The gasdermins are a family of recently identified pore-forming effector proteins that cause membrane permeabilization and pyroptosis, a lytic pro-inflammatory type of cell death. Gasdermins contain a cytotoxic N-terminal domain and a C-terminal repressor domain connected by a flexible linker. Proteolytic cleavage between these two domains releases the intramolecular inhibition on the cytotoxic domain, allowing it to insert into cell membranes and form large oligomeric pores, which disrupts ion homeostasis and induces cell death. Gasdermin-induced pyroptosis plays a prominent role in many hereditary diseases and (auto)inflammatory disorders as well as in cancer. In this Review, we discuss recent developments in gasdermin research with a focus on mechanisms that control gasdermin activation, pore formation and functional consequences of gasdermin-induced membrane permeabilization.

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Fig. 1: The gasdermin protein family.
Fig. 2: Role of gasdermin D in canonical and non-canonical inflammasome activation.
Fig. 3: Activation of gasdermins by ‘apoptotic’ caspases.
Fig. 4: Mechanism of gasdermin membrane insertion and pore formation.
Fig. 5: Immunological outcomes of gasdermin pore formation and pyroptosis.

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Acknowledgements

P.B. was supported by grants from the Swiss National Science Foundation (175576) and the European Research Council (ERC-2017-CoG 770988, InflamCellDeath). P.P. was supported by grants from Sociedad Española de Reumatología Pediátrica, Ministerio de Economia, Industria y Competitividad–Fondo Europeo de Desarrollo Regional (SAF2017–88276-R), Fundación Séneca (20859/PI/18) and the European Research Council (ERC-2013-CoG 614578). F.S. was supported by grants from China NSFC (81788101), MOST of China (2017YFA0505900 and 2016YFA0501500) and the Chinese Academy of Sciences (XDB08020202).

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Glossary

Inflammasome

A multi-protein signalling complex assembled in the cytosol upon detection of host-derived or pathogen-derived danger signals that promotes cytokine release, pyroptotic cell death and inflammation.

Caspases

A family of cysteine-dependent aspartate proteases that play a central role in cell death and inflammation by processing their substrates at specific aspartate residues.

Necrosis

A type of cell death in which the integrity of the plasma membrane is lost and the constituents of the cell are released.

NLRP3

(Nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3). A cytoplasmic sensor that assembles an inflammasome. NLRP3 is a broad-spectrum sensor of pathogen-associated and damage-associated molecular patterns.

Pannexin-1 channels

Plasma membrane channels permeable to ions and small metabolites such as ATP.

NETosis

A unique form of neutrophil cell death characterized by the release of DNA, histone and granular contents into the extracellular space.

Liposomes

Artificial spherical vesicles with at least one lipid bilayer composed of phospholipids.

Mitophagy

The selective removal of mitochondria by autophagy under conditions of nutrient starvation or mitochondrial stress.

ASC foci

(Apoptosis-associated speck-like protein containing a caspase recruitment domain foci). These multimeric protein aggregates result from helical fibril formation that is initiated by the homo-oligomerization of inflammasome proteins.

Familial Mediterranean fever

A genetically autosomal recessive inherited autoinflammatory disease arising from mutations in the MEFV gene, which encodes the protein pyrin, and is characterized by self-limited attacks of fever and serositis.

Pyrin

An inflammasome-forming cytoplasmic sensor of bacteria-induced RHO modifications and disruption of actin cytoskeleton dynamics. Pyrin is encoded by the MEFV gene.

Peroxisomes

Organelles of eukaryotic cells involved in the catabolism of different fatty acids and the reduction of reactive oxygen species.

NLRP1

(Nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 1). A cytoplasmic sensor that assembles an inflammasome. NLRP1 is activated by the N-end rule proteosomal degradation pathway.

NLRC4

(Nucleotide-binding oligomerization domain, leucine-rich repeat and caspase recruitment domain-containing 4). An inflammasome scaffold protein that oligomerizes upon binding to the inflammasome sensor — the NLR family apoptosis inhibitory protein (NAIP) — and forms a platform to activate caspase 1.

Toll-like receptor

A class of pattern recognition receptor located at endosomal and plasma membranes that senses pathogen-associated and damage-associated molecular patterns and initiates signalling pathways to induce inflammation.

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Broz, P., Pelegrín, P. & Shao, F. The gasdermins, a protein family executing cell death and inflammation. Nat Rev Immunol 20, 143–157 (2020). https://doi.org/10.1038/s41577-019-0228-2

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