Coral gasdermin triggers pyroptosis

Jiang, Shuai; Zhou, Zhi; Sun, Yuanyuan; Zhang, Tengfei; Sun, Li

doi:10.1126/sciimmunol.abd2591

Cited by 74 publications

(61 citation statements)

References 44 publications

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“…S6B). This finding and the conclusion that the ancestral proto-gasdermin was pore forming is further supported by the results reported for the recently described GSDM NT of the coral Orbicella faveolata [ 36 ]. It is important to highlight that while bf-GSDM NT and sh-GSDME NT resulted in a similar Yo-Pro-1 uptake and IL-1β release when compared to mm-GSDMD NT , the release of LDH (a tetrameric protein) was significantly lower (Fig.…”

Section: Resultssupporting

confidence: 86%

“…Since pyroptotic cell death is an evolutionarily conserved function of gasdermins in response to infection [ 36 ], we next aimed to analyze the expression of the different gasdermins in different mouse tissues during a cecal ligation and puncture (CLP)-induced model of sepsis. Basal expression of mm- gsdma1 and mm- gsdmc was found in the skin and intestines, mm- gsdmd expression was found in the lung and intestines, while basal mm- gsdme expression was found in the intestines, kidney, bone marrow, brain, and cerebellum (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…This places doubt on whether the ancestral gasdermin protein was a lytic protein. However, a recent study found that coral GSDM NT is highly lytic and induces high levels of LDH release [ 36 ]. This suggests that ancestral Chordata gasdermins were less efficient at inducing cell death and that maybe the pores produced by them could be more efficiently excised from the plasma membrane by different mechanisms, including the endosomal sorting complexes required for transport machinery that has been shown to be able to remove GSDMD pores from the plasma membrane [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

“…In invertebrates, the lytic function of the N-terminal sequence of gasdermins has been demonstrated for the coral gasdermin that is activated after caspase-3 cleavage during infection and that induces cell death [ 36 ]. In our study, we found that the N-terminal sequences of distantly related Chordata species (lancelet and shark) also induce a cell death characterized by plasma membrane permeability.…”

Section: Discussionmentioning

confidence: 99%

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Evolutionary analyses of the gasdermin family suggest conserved roles in infection response despite loss of pore-forming functionality

et al. 2022

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Background Gasdermins are ancient (>500million-years-ago) proteins, constituting a family of pore-forming proteins that allow the release of intracellular content including proinflammatory cytokines. Despite their importance in the immune response, and although gasdermin and gasdermin-like genes have been identified across a wide range of animal and non-animal species, there is limited information about the evolutionary history of the gasdermin family, and their functional roles after infection. In this study, we assess the lytic functions of different gasdermins across Metazoa species, and use a mouse model of sepsis to evaluate the expression of the different gasdermins during infection. Results We show that the majority of gasdermin family members from distantly related animal clades are pore-forming, in line with the function of the ancestral proto-gasdermin and gasdermin-like proteins of Bacteria. We demonstrate the first expansion of this family occurred through a duplication of the ancestral gasdermin gene which formed gasdermin E and pejvakin prior to the divergence of cartilaginous fish and bony fish ~475 mya. We show that pejvakin from cartilaginous fish and mammals lost the pore-forming functionality and thus its role in cell lysis. We describe that the pore-forming gasdermin A formed ~320 mya as a duplication of gasdermin E prior to the divergence of the Sauropsida clade (the ancestral lineage of reptiles, turtles, and birds) and the Synapsid clade (the ancestral lineage of mammals). We then demonstrate that the gasdermin A gene duplicated to form the rest of the gasdermin family including gasdermins B, C, and D: pore-forming proteins that present a high variation of the exons in the linker sequence, which in turn allows for diverse activation pathways. Finally, we describe expression of murine gasdermin family members in different tissues in a mouse sepsis model, indicating function during infection response. Conclusions In this study we explored the evolutionary history of the gasdermin proteins in animals and demonstrated that the pore-formation functionality has been conserved from the ancient proto-gasdermin protein. We also showed that one gasdermin family member, pejvakin, lost its pore-forming functionality, but that all gasdermin family members, including pejvakin, likely retained a role in inflammation and the physiological response to infection.

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Section: Resultssupporting

confidence: 86%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Evolutionary analyses of the gasdermin family suggest conserved roles in infection response despite loss of pore-forming functionality

et al. 2022

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“…Gasdermin activation requires caspase- or granzyme-mediated cleavage of an inter-domain linker that liberates a lipophilic N-terminal domain (NTD) from a large inhibitory C-terminal domain (CTD) ( 4–6 ). Proteolysis enables gasdermin NTD oligomerization and rapid formation of membrane pores, which have emerged as an important component of innate immune defense in mammals and primitive eukaryotes ( 7–9 ). Recent structural analyses explain a mechanism of gasdermin pore formation ( 5, 6, 10, 11 ), but the evolutionary origin and biological roles of diverse gasdermin proteins remain unknown ( 12 ).…”

Section: Main Textmentioning

confidence: 99%

Bacterial gasdermins reveal an ancient mechanism of cell death

Johnson

Wein

Mayer

et al. 2021

Preprint

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Gasdermin proteins form large membrane pores in human cells that release immune cytokines and induce lytic cell death. Gasdermin pore formation is triggered by caspase-mediated cleavage during inflammasome signaling and is critical for defense against pathogens and cancer. Here we discover gasdermin homologs encoded in bacteria that execute prokaryotic cell death. Structures of bacterial gasdermins reveal a conserved pore-forming domain that is stabilized in the inactive state with a buried lipid modification. We demonstrate that bacterial gasdermins are activated by dedicated caspase-like proteases that catalyze site-specific cleavage and removal of an inhibitory C-terminal peptide. Release of autoinhibition induces the assembly of >200 Å pores that form a mesh-like structure and disrupt membrane integrity. These results demonstrate that caspase-mediated activation of gasdermins is an ancient form of regulated cell death shared between bacteria and animals.

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