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

Angosto-Bazarra, Diego; Alarcón‐Vila, Cristina; Hurtado-Navarro, Laura; Baños, María C; Rivers-Auty, Jack; Pelegrı́n, Pablo

doi:10.1186/s12915-021-01220-z

Cited by 46 publications

(36 citation statements)

References 82 publications

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“…Different from GSDMA-E, GSDMF is composed of a conserved NT domain and a very short CT domain. GSDMF exhibits no pyroptosis-inducing capacity, but was reported to be involved in peroxisome homeostasis (Defourny et al, 2019;Angosto-Bazarra et al, 2022). During pyroptosis, GSDM is cleaved by a protease, and the cleavage releases the NT fragment that induces cell death by forming pores on the plasma membrane (Ding et al, 2016;Evavold et al, 2018;Liu et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

New insights into the evolutionary dynamic and lineage divergence of gasdermin E in metazoa

Yuan

Jiang

Qin

et al. 2022

Front. Cell Dev. Biol.

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Gasdermin (GSDM) is a family of pore-forming proteins that induce pyroptosis. To date, the origin and evolution of GSDM in Metazoa remain elusive. Here, we found that GSDM emerged early in Placozoa but is absent in a large number of invertebrates. In the lower vertebrate, fish, three types of GSDME, i.e., GSDMEa, GSDMEb, and a previously unreported type (designated GSDMEc), were idenitied. Evolutionarily, the three GSDMEs are distinctly separated: GSDMEa is closely related to tetrapod GSDME; GSDMEb exists exclusively in fish; GSDMEc forms the lineage root of tetrapod GSDMA/B/C/D. GSDMEc shares conserved genomic features with and is probably the prototype of GSDMA, which we found existing in all tetrapod classes. GSDMEc displays fast evolutionary dynamics, likely as a result of genomic transposition. A cross-metazoan analysis of GSDME revealed that GSDMEa shares a conserved caspase recognition motif with the GSDME of tetrapods and cnidarians, whereas GSDMEb has a unique caspase recognition motif similar to that of mammalian GSDMD, and GSDMEc exhibits no apparent caspase recognition motif. Through functional test, four highly conserved residues in vertebrate GSDME proved to be essential to auto-inhibition. Together our results provide new insights into the origin, evolution, and function of metazoan GSDMs.

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Section: Introductionmentioning

confidence: 99%

New insights into the evolutionary dynamic and lineage divergence of gasdermin E in metazoa

Yuan

Jiang

Qin

et al. 2022

Front. Cell Dev. Biol.

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“…A role for GSDME-induced pyroptosis and bactericidal activity in the marine teleost Cynoglossus semilaevis has also been proposed through its cleavage by caspase-1 and to a lesser extent caspase-3/7, with preservation of caspase-1 cleavage of GSDME being observed in many teleost species [ 106 ]. Furthermore, while GSDMA-GSDMD orthologs appear restricted to mammals, phylogenetic analysis of GSDME in invertebrates, including hydra, molluscs, brachiopods, corals, and sea anemones indicates a closer relation to mammalian DFNB59 (or PJVK) which, unlike other mammalian gasdermins, does not cause pyroptosis when the N-terminal fragment is expressed in cell lines [ 31 ]. Recent work reported a gasdermin N-terminal homolog, regulator of cell death 1 (RCD1), in the filamentous fungi Neurospora crassa , which like gasdermins localizes to peripheral cell margins, interacts with phospholipids including cardiolipin and when expressed in 293T kidney cells, can induce a pyroptosis-like death [ 107 ].…”

Section: Apoptotic Activation Of Pyroptosis By Caspase-3 Cleavage Of ...mentioning

confidence: 99%

“…Recent work reported a gasdermin N-terminal homolog, regulator of cell death 1 (RCD1), in the filamentous fungi Neurospora crassa , which like gasdermins localizes to peripheral cell margins, interacts with phospholipids including cardiolipin and when expressed in 293T kidney cells, can induce a pyroptosis-like death [ 107 ]. Although these results illustrate similarities in cell death execution proteins between the fungal and animal kingdoms, the level of RCD1 sequence identity with mammalian gasdermins has been disputed, and the lack of Rcd genes in organisms beyond fungi and bacteria have led others to suggest that RCD1 should not be considered a gasdmerin family member [ 31 ]. Regardless, it appears that, at least functionally, gasdermin-like pore-forming proteins predate the metazoan era.…”

Section: Apoptotic Activation Of Pyroptosis By Caspase-3 Cleavage Of ...mentioning

confidence: 99%

“…These gasdermins are generally composed of a N-terminal pore-forming domain, though the gasdermin family member Pejvakin (PJVK) is an exception to this, an interdomain linker that is cleaved to unleash gasdermin activity, and an autoinhibitory C-terminal domain. The pore-forming ability of the N-terminal domain of gasdermin proteins is highly conserved, with mammalian pore-forming family members (GSDMA-E) having arisen from genetic duplications of a gasdermin gene present in ancient metazoans, suggesting a high degree of evolutionary pressure [ 30 , 31 ]. Experimental studies also show that the N-terminal domain of coral and lancelet gasdermin are both capable of causing pyroptosis, indicating that gasdermin function is conserved beyond mammals [ 31 , 32 ].…”

Section: Introductionmentioning

confidence: 99%

“…The pore-forming ability of the N-terminal domain of gasdermin proteins is highly conserved, with mammalian pore-forming family members (GSDMA-E) having arisen from genetic duplications of a gasdermin gene present in ancient metazoans, suggesting a high degree of evolutionary pressure [ 30 , 31 ]. Experimental studies also show that the N-terminal domain of coral and lancelet gasdermin are both capable of causing pyroptosis, indicating that gasdermin function is conserved beyond mammals [ 31 , 32 ].…”

Section: Introductionmentioning

confidence: 99%

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No longer married to inflammasome signaling: the diverse interacting pathways leading to pyroptotic cell death

Weir

Vince

2022

Biochemical Journal

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For over 15 years the lytic cell death termed pyroptosis was defined by its dependency on the inflammatory caspase, caspase-1, which, upon pathogen sensing, is activated by innate immune cytoplasmic protein complexes known as inflammasomes. However, this definition of pyroptosis changed when the pore-forming protein gasdermin D (GSDMD) was identified as the caspase-1 (and caspase-11) substrate required to mediate pyroptotic cell death. Consequently, pyroptosis has been redefined as a gasdermin-dependent cell death. Studies now show that, upon liberation of the N-terminal domain, five gasdermin family members, GSDMA, GSDMB, GSDMC, GSDMD and GSDME can all form plasma membrane pores to induce pyroptosis. Here, we review recent research into the diverse stimuli and cell death signaling pathways involved in the activation of gasdermins; death and toll-like receptor triggered caspase-8 activation of GSDMD or GSMDC, apoptotic caspase-3 activation of GSDME, perforin-granzyme A activation of GSDMB, and bacterial protease activation of GSDMA. We highlight findings that have begun to unravel the physiological situations and disease states that result from gasdermin signaling downstream of inflammasome activation, death receptor and mitochondrial apoptosis, and necroptosis. This new era in cell death research therefore holds significant promise in identifying how distinct, yet often networked, pyroptotic cell death pathways might be manipulated for therapeutic benefit to treat a range of malignant conditions associated with inflammation, infection and cancer.

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The pathogenesis and potential therapeutic targets in sepsis

Zhang,

Jiang,

et al. 2023

MedComm

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Sepsis is defined as “a life‐threatening organ dysfunction caused by dysregulated host systemic inflammatory and immune response to infection.” At present, sepsis continues to pose a grave healthcare concern worldwide. Despite the use of supportive measures in treating traditional sepsis, such as intravenous fluids, vasoactive substances, and oxygen plus antibiotics to eradicate harmful pathogens, there is an ongoing increase in both the morbidity and mortality associated with sepsis during clinical interventions. Therefore, it is urgent to design specific pharmacologic agents for the treatment of sepsis and convert them into a novel targeted treatment strategy. Herein, we provide an overview of the molecular mechanisms that may be involved in sepsis, such as the inflammatory response, immune dysfunction, complement deactivation, mitochondrial damage, and endoplasmic reticulum stress. Additionally, we highlight important targets involved in sepsis‐related regulatory mechanisms, including GSDMD, HMGB1, STING, and SQSTM1, among others. We summarize the latest advancements in potential therapeutic drugs that specifically target these signaling pathways and paramount targets, covering both preclinical studies and clinical trials. In addition, this review provides a detailed description of the crosstalk and function between signaling pathways and vital targets, which provides more opportunities for the clinical development of new treatments for sepsis.

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

Cited by 46 publications

References 82 publications

New insights into the evolutionary dynamic and lineage divergence of gasdermin E in metazoa

New insights into the evolutionary dynamic and lineage divergence of gasdermin E in metazoa

No longer married to inflammasome signaling: the diverse interacting pathways leading to pyroptotic cell death

The pathogenesis and potential therapeutic targets in sepsis

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