Streptococcal pyrogenic exotoxin B cleaves GSDMA and triggers pyroptosis

Deng, Wanyan; Bai, Yang; Deng, Fan; Pan, Ying; Mei, Shenglin; Zheng, Zengzhang; Min, Rui; Wu, Zeyu; Wu, Li; Miao, Rong; Zhang, Zhibin; Kupper, Thomas S.; Lieberman, Judy; Liu, Xing

doi:10.1038/s41586-021-04384-4

Cited by 218 publications

(160 citation statements)

References 39 publications

Supporting

Mentioning

158

Contrasting

Order By: Relevance

“…The N-terminal of GSDMA3 (three homologs of GSDMA exist in mice) forms pores with a diameter of ∼180 Å and, similar to GSDMD, GSDMA binds phosphoinositides and cardiolipin [ 40 , 43 , 147 ]. Recent research has uncovered how GSDMA, which is highly expressed in the skin epithelia, is activated by group A Streptococcus (GAS) via the bacterial protease SpeB, which processes GSDMA after Q246 in the linker region to unleash the N-terminal pore-forming fragment [ 148 ] ( Figure 2 ). Mice lacking GSDMA1 showed increased systemic infection and mortality upon infection with GAS, highlighting the important role of GSDMA in sensing pathogen virulence factors to protect the host.…”

Section: Bacterial Activation Of Gsdma To Trigger Pyroptotic Deathmentioning

confidence: 99%

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

Weir

Vince

2022

Biochemical Journal

View full text Add to dashboard Cite

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.

show abstract

Section: Bacterial Activation Of Gsdma To Trigger Pyroptotic Deathmentioning

confidence: 99%

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

Weir

Vince

2022

Biochemical Journal

View full text Add to dashboard Cite

show abstract

“…Originally, as a pro-inflammatory form of PCD, pyroptosis was known for mediation by pro-inflammatory caspases, including caspase-1 that often activated by canonical inflammasomes, and caspase-4/5/11 that often activated by non-canonical inflammasomes ( Latz et al., 2013 ; Khan et al., 2018 ). But more recently, pyroptosis was also shown to be mediated by virulence factors, granzyme and pro-apoptotic caspases, suggesting pro-inflammatory caspases are not the unique inducer of pyroptosis ( Wang et al., 2017 ; Zhou et al., 2020 ; Deng et al., 2022 ). Pyroptosis has been defined as a type of PCD relying on gasdermin protein family, which is the most notable feature distinguished from other PCDs ( Shi et al., 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Campylobacter jejuni Cytolethal Distending Toxin Induces GSDME-Dependent Pyroptosis in Colonic Epithelial Cells

Yang

Wang

et al. 2022

Front. Cell. Infect. Microbiol.

View full text Add to dashboard Cite

BackgroundCytolethal distending toxin (CDT) is a critical virulence factor of Campylobacter jejuni, and it induces cell death and regulates inflammation response in human epithelial cells. Pyroptosis is an inflammatory form of programmed cell death (PCD), but whether it is involved in CDT-mediated cytotoxicity remains elusive.AimsThis study explores the role and mechanism of pyroptosis in CDT-mediated cytotoxicity.MethodsHCT116 and FHC cell lines were treated with CDT. Cell Counting Kit-8 (CCK-8) assay was used to detect cell viability. Western blotting was used to measure the expression of related proteins in the pathway, and cell morphology observation, annexin V/propidium iodide (PI) staining and lactate dehydrogenase (LDH) release assay were performed to evaluate the occurrence of pyroptosis.ResultOur results show that C. jejuni CDT effectively induces pyroptosis in a dose- and time- dependent manner in human colonic epithelial cells owing to its DNase activity. Specific pyroptotic features including large bubbles emerging from plasma membrane and LDH release were observed upon CDT treatment. Moreover, CDT-induced pyroptosis involves the caspase-9/caspase-3 axis, which is followed by gasdermin E (GSDME) cleavage rather than gasdermin D (GSDMD). N-acetyl cysteine (NAC), a reactive oxygen species (ROS) inhibitor, attenuates the activation of caspase-9/3, the cleavage of GSDME and pyroptotic characteristic, therefore demonstrating ROS initiates pyroptotic signaling.ConclusionsWe first clarify a molecular mechanism that CDT induces pyroptosis via ROS/caspase-9/caspase-3/GSDME signaling. These findings provide a new insight on understanding of CDT-induced pathogenesis at the molecular level.

show abstract

“…[1][2][3][4] Pyroptosis is tightly regulated by the assembly of canonical or non-canonical inflammasomes and the activation or presence of certain caspases, granzymes or pathogenic proteases. [5][6][7][8][9] In turn, these proteases activate gasdermins by cleaving off their C-terminal domains, which exposes a basic surface on the N-terminal domain. 3,7 The Nterminal domain then binds to the plasma membrane, oligomerizes, and inserts a β-sheet into the membrane, similar to bacterial β pore-forming toxins 10 though acting from the inner leaflet.…”

Section: Introductionmentioning

confidence: 99%

Sublytic gasdermin-D pores captured in atomistic molecular simulations

Schaefer

Hummer

2022

Preprint

View full text Add to dashboard Cite

Gasdermin-D (GSDMD) is the ultimate effector of pyroptosis, a form of programmed cell death associated with pathogen invasion and inflammation. After proteolytic cleavage by caspases activated by the inflammasome, the GSDMD N-terminal domain (GSDMDNT) assembles on the inner leaflet of the plasma membrane and induces the formation of large membrane pores. We use atomistic molecular dynamics simulations to study GSDMDNT monomers, oligomers, and rings in an asymmetric plasma membrane mimetic. We identify distinct interaction motifs of GSDMDNT with phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) and phosphatidylserine (PS) headgroups and describe differential lipid binding between the pore and prepore conformations. Oligomers are stabilized by shared lipid binding sites between neighboring monomers acting akin to double-sided tape. We show that already small GSDMDNT oligomers form stable, water-filled and ion-conducting membrane pores bounded by curled beta-sheets. In large-scale simulations, we resolve the process of pore formation by lipid detachment from GSDMDNT arcs and lipid efflux from partial rings. We find that that high-order GSDMDNT oligomers can crack under the line tension of 86 pN created by an open membrane edge to form the slit pores or closed GSDMDNT rings seen in experiment. Our simulations provide a detailed view of key steps in GSDMDNT-induced plasma membrane pore formation, including sublytic pores that explain nonselective ion flux during early pyroptosis.

show abstract

Streptococcal pyrogenic exotoxin B cleaves GSDMA and triggers pyroptosis

Cited by 218 publications

References 39 publications

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

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

Campylobacter jejuni Cytolethal Distending Toxin Induces GSDME-Dependent Pyroptosis in Colonic Epithelial Cells

Sublytic gasdermin-D pores captured in atomistic molecular simulations

Contact Info

Product

Resources

About