Formation of membrane pores by gasdermin-N causes pyroptosis

Qi, Xiaopeng

doi:10.1007/s11427-016-5109-3

Cited by 11 publications

(6 citation statements)

References 9 publications

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“…These results suggest that the increases in levels of circulating autoantigens in GSDMD −/− mice are most likely driven by peripheral myeloid cell expansion and through differential modulation of certain types of cell death, rather than through impaired clearance of dead cells or their products. As GSDMD is essential for pyroptosis, this type of cell death would not represent a mechanism leading to enhanced generation of released nucleic acids in the knockout mice (18)(19)(20)(21). Moreover, as men tioned before, we did not find a difference in NET formation (Sup plementary Figure 5).…”

Section: Effects Of Gsdmd Deficiency On Specific Pro In Flammatory Cesupporting

confidence: 65%

“…The molecule gasdermin D (GSDMD) has been described as the key executioner of pyroptosis, a proinflammatory form of programmed cell death that occurs most frequently following infections with intracellular pathogens and that is linked to inflam masome activation (17)(18)(19)(20). After activation through cleavage by caspases, the GSDMD Nterminal domain can oligomerize to form membrane pores and promote the release of intracellular contents, including the proinflammatory cytokines interleukin1β (IL1β) and IL18, both of which generate an inflammasome associated inflammatory response (21)(22)(23). In addition to pyrop tosis, GSDMD was recently implicated in the formation of NETs in the context of microbial inflammation (24)(25)(26) and in the regu lation of apoptosis through the formation of mitochondrial pores and subsequent release of cytochrome c from the mitochondria (27,28).…”

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confidence: 99%

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Effects of Gasdermin D in Modulating Murine Lupus and its Associated Organ Damage

Wang

Blanco

Carmona‐Rivera

et al. 2020

Arthritis & Rheumatology

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Objective Gasdermin D (GSDMD) is the key executioner of an inflammatory cell death mechanism known as pyroptosis. Recent reports have also implicated GSDMD in other mechanisms of cell death, including apoptosis, necroptosis, and NETosis. Given the role of dysregulated cell death in autoimmune syndromes such as systemic lupus erythematosus (SLE), this study was undertaken in a murine lupus model to investigate whether GSDMD plays a pathogenic role in systemic autoimmunity by promoting inflammatory cell death, leading to increased generation of nuclear autoantigens and autoantibodies. Methods An imiquimod‐induced model of SLE was tested in GSDMD−/− mice (n = 30), with wild‐type (WT) mice as controls (n = 34), on a C57BL/6 background. At the time of euthanasia, the mice were examined for serum autoantibodies, immune complex deposition, organ inflammation, immune dysregulation, and type I interferon responses. A model of pristane‐induced lung injury in GSDMD−/− mice (n = 7), with WT mice as controls (n = 10), was used to confirm the pulmonary phenotype. Regulation of various mechanisms of cell death by GSDMD was investigated in the mice. Results Unexpectedly, GSDMD−/− mice developed enhanced mortality, more severe renal and pulmonary inflammation, and exacerbated autoantibody production in response to imiquimod. Pulmonary involvement was also more severe in the absence of GSDMD in mice with pristane‐induced lung injury. Compared to WT mice, lack of GSDMD was associated with increased levels of circulating nuclear autoantigens (P < 0.01), anti–double‐stranded DNA autoantibodies (P < 0.01), tissue immune complex deposition (P < 0.05), expansion of myeloid cell subsets (P < 0.05), and enhanced B cell activation and plasma cell differentiation (P = 0.001). Moreover, in the absence of GSDMD, enhanced autoantigen generation was associated with increased local induction of cell death in vivo. Conclusion GSDMD negatively regulates autoantigen generation and immune dysregulation in response to tissue injury and may play previously unappreciated protective roles in systemic autoimmunity.

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Section: Effects Of Gsdmd Deficiency On Specific Pro In Flammatory Cesupporting

confidence: 65%

mentioning

confidence: 99%

Effects of Gasdermin D in Modulating Murine Lupus and its Associated Organ Damage

Wang

Blanco

Carmona‐Rivera

et al. 2020

Arthritis & Rheumatology

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“…Pyroptosis is the maturity and excretion of proinflammatory cytokines IL-1β/18 controlled by Inflammasomes and an inflammatory cell death mode induced by Inflammasomes. 31 Inflammasomes also act as an activation platform for procaspase-1. 32 Unlike LPS, TNF-α did not induce pyroptosis.…”

Section: Discussionmentioning

confidence: 99%

<p>LPS Enhances the Chemosensitivity of Oxaliplatin in HT29 Cells via GSDMD-Mediated Pyroptosis</p>

Liu

Wang

et al. 2020

CMAR

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Introduction: Pyroptosis induced by lipopolysaccharide (LPS) is a dissolved form of cell death. The molecular marker gasdermin D, specifically GSDMD-N, is critically required for the induction of pyroptosis. Recently, there have been studies showing that LPS is closely related to tumor biology. Methods: Specimens from 40 patients with colorectal cancer (CRC) were collected. Eight-to twelve-week-old C57BL6 male mice (n=30) were raised. Immunohistochemistry and Western blot were performed to test the expression of GSDMD. Moreover, cytotoxicity assay, IL-18 and IL-1β ELISA, Annexin V and PI stain, and wound healing assay were also made. Gene Expression Profiling Interactive Analysis (GEPIA) was used to verify the expression of GSDMD and overall survival of CRC patients with a high/low expression of GSDMD. Results: In the research, we showed that the poor prognosis in CRC patients was significantly related to the GSDMD expression and significantly down-regulated in human colorectal cancer (CRC) tissues. Treatment with LPS, but not TNF-α, induced pyroptosis via promoting the expression of GSDMD and GSDMD-N membrane translocation and enhanced chemosensitivity in response to L-OHP in HT29 cells. Furthermore, the enforced expression of GSDMD in HT29 cells reduced cell survival and induced cell death. Discussion: These results of studies suggest that the low expression of GSDMD correlates with a poor CRC prognosis, and that pyroptosis induced by LPS may improve the anti-cancer effect of L-OHP, inhibiting the tumorigenesis of CRC by activating GSDMD. Our findings lay the foundation for further development of GSDMD serving as an important prognostic biomarker and a valid CRC therapeutic target.

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“…Pyroptosis, another form of inflammatory programmed necrotic cell death, was recently defined mediated by gasdermin family members. Gasdermin D (GSDMD) functions downstream of caspases-1 and caspases-11 to execute pyroptosis through pore formation on the membrane [32][33][34][35]. It is not known whether type I IFN also controls necroptosis and pyroptosis through additional mechanisms in response to A. baumannii infection.…”

Section: Type I Ifn Controls the Transcription Of Key Mediators Of Nementioning

confidence: 99%

Type I IFN operates pyroptosis and necroptosis during multidrug-resistant A. baumannii infection

Guo

et al. 2018

Cell Death Differ

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Multidrug-resistant Acinetobacter baumannii, a common pathogen responsible for nosocomial infections, is the main cause for outbreaks of infectious diseases, such as pneumonia, meningitis, and bacteremia, especially among critically ill patients. Epidemic A. baumannii is a growing public health concern as it is resistant to all existing antimicrobial agents, thereby necessitating the development of new therapeutic approaches to mount an effective immune response against this bacterial pathogen. In this study, we identified a critical role for type I interferon (IFN) in epigenetic regulation during A. baumannii infection and established a central role for it in multiple cell death pathways. A. baumannii infection induced mixed cell death constituted of apoptosis, pyroptosis, and necroptosis. Mechanically, A. baumannii triggered TRIF-dependent type I IFN production, which in turn induced the expression of genes Zbp1, Mlkl, caspase-11, and Gsdmd via KAT2B-mediated and P300-mediated H3K27ac modification, leading to NLRP3 inflammasome activation, and potentially contributed to GSDMD-mediated pyroptosis and MLKL-dependent necroptosis. Our study offers novel insights into the mechanisms of type I IFN and provides potential therapeutic targets for infectious and inflammatory diseases.

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Formation of membrane pores by gasdermin-N causes pyroptosis

Cited by 11 publications

References 9 publications

Effects of Gasdermin D in Modulating Murine Lupus and its Associated Organ Damage

Effects of Gasdermin D in Modulating Murine Lupus and its Associated Organ Damage

<p>LPS Enhances the Chemosensitivity of Oxaliplatin in HT29 Cells via GSDMD-Mediated Pyroptosis</p>

Type I IFN operates pyroptosis and necroptosis during multidrug-resistant A. baumannii infection

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