Pyroptotic gasdermin exists in Mollusca and is vital to eliminating bacterial infection

Qin, Kunpeng; Jiang, Shuai; Xu, Hang; Yuan, Zihao; Sun, Li

doi:10.1016/j.celrep.2023.112414

Cited by 18 publications

(9 citation statements)

References 52 publications

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“…Near the midpoint of our tree is a gasdermin that is preserved in mollusks, coral, hydras, and other invertebrates referred to as GSDM in . For such species, caspase-3 cleaves this gasdermin to execute pyroptosis, much like GSDME ( Jiang et al, 2020 ; Qin et al, 2023 ; Chen et al, 2023 ).…”

Section: Resultsmentioning

confidence: 99%

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Caspase-1 activates gasdermin A in non-mammals

Billman,

Kovacs,

Wei

et al. 2024

eLife

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Gasdermins oligomerize to form pores in the cell membrane, causing programmed lytic cell death called pyroptosis. Mammals encode five gasdermins that can trigger pyroptosis: GSDMA, B, C, D, and E. Caspase and granzyme proteases cleave the linker regions of and activate GSDMB, C, D, and E, but no endogenous activation pathways are yet known for GSDMA. Here, we perform a comprehensive evolutionary analysis of the gasdermin family and focus on the first gene amplification event that gave rise to mammal GSDMA-D by studying GSDMA in non-mammal species including amphibians, reptiles, and birds. Remarkably, GSDMA in numerous bird species contains the canonical caspase-1 cleavage site YVAD in the linker. We show that GSDMA from birds, amphibians, and reptiles are all cleaved by caspase-1. Thus, GSDMA was originally cleaved by the host-encoded protease caspase-1. In mammals the caspase-1 cleavage site in GSDMA is disrupted; instead, a new protein, GSDMD, is the target of caspase-1. Mammal caspase-1 uses exosite interactions with the GSDMD C-terminal domain to confer the specificity of this interaction, whereas we show that bird caspase-1 uses a stereotypical tetrapeptide sequence to confer specificity for bird GSDMA. Our results reveal an evolutionarily stable association between caspase-1 and the gasdermin family, albeit a shifting one. Caspase-1 repeatedly changes its target gasdermin over evolutionary time at speciation junctures, initially cleaving GSDME in fish, then GSDMA in amphibians/reptiles/birds, and finally GSDMD in mammals. We demonstrate that amphibians, reptiles and birds engage pyroptosis using caspase-1 and GS-DMA, filling an evolutionary gap in which caspase-1 cleaves GSDME in fish and GSDMD in mammals.

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Section: Resultsmentioning

confidence: 99%

“…This is similar to how cnidarian and mollusk GSDM release two N-terminal fragments when cleaved by caspase-3. Interestingly, in those species, both fragments are competent to form pores ( Jiang et al, 2020 ; Qin et al, 2023 ). Alternatively, the second cleavage may be an inactivation site ( Xu et al, 2022 ; Taabazuing et al, 2017 ).…”

Section: Resultsmentioning

confidence: 99%

Caspase-1 activates gasdermin A in non-mammals

Billman,

Kovacs,

Wei

et al. 2024

eLife

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show abstract

“…Near the midpoint of our tree is a gasdermin is preserved in mollusks, coral, hydras and other invertebrates as a functional equivalent of GSDME, sometimes referred to as GSDM in . For such species, caspase-3 cleaves this gasdermin to execute pyroptosis ( Jiang et al, 2020 ; Qin et al, 2023 ; Chen et al, 2023 ).…”

Section: Resultsmentioning

confidence: 99%

“…Both birds and mammals encode caspases-1 and −3. In species with as distant common ancestors as coral, GDSME is cleaved by caspase-3 ( Qin et al, 2023 ; Chen et al, 2023 ; Jiang et al, 2020 ). In mammals, caspase-3 inactivates GSDMD by cleaving within the N-terminal pore forming domain to prevent pore formation during apoptosis.…”

Section: Resultsmentioning

confidence: 99%

Caspase-1 activates gasdermin A in non-mammals

Billman,

Kovacs,

Wei

et al. 2023

Preprint

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Gasdermins oligomerize to form pores in the cell membrane, causing programmed lytic cell death called pyroptosis. Mammals encode five gasdermins that can trigger pyroptosis: GSDMA, B, C, D, and E. Caspase and granzyme proteases cleave the linker regions of and activate GSDMB, C, D, and E, but no endogenous activation pathways are yet known for GSDMA. Here, we perform a comprehensive evolutionary analysis of the gasdermin family and focus on the first gene amplification event that gave rise to mammalGSDMA-Dby studying GSDMA in non-mammal species including amphibians, reptiles, and birds. Remarkably, GSDMA in numerous bird species contains the canonical caspase-1 cleavage site YVAD in the linker. We show that GSDMA from birds, amphibians, and reptiles are all cleaved by caspase-1. Thus, GSDMA was originally cleaved by the host-encoded protease caspase-1. In mammals the caspase-1 cleavage site in GSDMA is disrupted; instead, a new protein, GSDMD, is the target of caspase-1. Mammal caspase-1 uses exosite interactions with the GSDMD C-terminal domain to confer the specificity of this interaction, whereas we show that bird caspase-1 uses a stereotypical tetrapeptide sequence to confer specificity for bird GSDMA. Our results reveal an evolutionarily stable association between caspase-1 and the gasdermin family, albeit a shifting one. Caspase-1 repeatedly changes its target gasdermin over evolutionary time at speciation junctures, initially cleaving GSDME in fish, then GSDMA in amphibians/reptiles/birds, and finally GSDMD in mammals.One Sentence SummaryWe demonstrate that amphibians, reptiles and birds engage pyroptosis using caspase-1 and GS-DMA, filling an evolutionary gap in which caspase-1 cleaves GSDME in fish and GSDMD in mammals.

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“…GSDMs and GSDM-like proteins are present in all vertebrates and some invertebrates, including lancelets, Mollusca, and even Cnidaria (3,(24)(25)(26)(27)(28). Invertebrate GSDMs also adopt an autoinhibited two-domain organization; their pore-forming pyroptotic activities are unleashed upon interdomain cleavage by caspases from the cognate organisms (25)(26)(27). Recently, functional GSDM-like proteins (sharing little sequence homologies to metazoan GSDMs) were noted in bacteria and fungi (29)(30)(31).…”

mentioning

confidence: 99%

Cleavage-independent activation of ancient eukaryotic gasdermins and structural mechanisms

Li,

Hou,

Sun

et al. 2024

Science

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Gasdermins (GSDMs) are pore-forming proteins that execute pyroptosis for immune defense. GSDMs are two-domain proteins, activated by proteolytic removal of the inhibitory domain. Here we report two types of cleavage-independent GSDM activation. First, Tricho GSDM, a pore-forming-domain-only protein from the basal metazoan Trichoplax adhaerens , is a disulfides-linked autoinhibited dimer, activated by reduction of the disulfides. Cryo–electron microscopy (cryo-EM) structure illustrates assembly mechanism for the 44-mer Tricho GSDM pore. Second, RCD-1-1/RCD-1-2, encoded by polymorphic rcd-1 in filamentous fungus Neurospora crassa , are also pore-forming-domain-only GSDMs. RCD-1-1 and RCD-1-2, when encountering each other, form pores and cause pyroptosis, underlying allorecognition in Neurospora . Cryo-EM structure reveals a pore of 11 RCD-1-1/RCD-1-2 heterodimers and heterodimerization-triggered pore assembly mechanism. This study shows mechanistic diversities in GSDM activation and indicates versatile functions of GSDMs.

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Pyroptotic gasdermin exists in Mollusca and is vital to eliminating bacterial infection

Cited by 18 publications

References 52 publications

Caspase-1 activates gasdermin A in non-mammals

Caspase-1 activates gasdermin A in non-mammals

Caspase-1 activates gasdermin A in non-mammals

Cleavage-independent activation of ancient eukaryotic gasdermins and structural mechanisms

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