Pyroptosis: Gasdermin-Mediated Programmed Necrotic Cell Death

Shi, Jianjin; Gao, Wenqing; Shao, Feng

doi:10.1016/j.tibs.2016.10.004

Cited by 1,993 publications

(1,487 citation statements)

References 76 publications

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“…Recently, GSDMD has been identified as a key determinant of pyroptosis (24)(25)(26)(27). To investigate the impact of EV71 infection, we analyzed the expression of GSDMD.…”

Section: Resultsmentioning

confidence: 99%

“…Pyroptosis is a form of programmed necrosis that features pore formation in the plasma membrane, cell swelling, and lysis and releases cytoplasmic content to the extracellular environment (20)(21)(22). Its initiation depends on the activation of inflammatory caspases, such caspase-1, caspase-4, and caspase-5 in humans (23,24), leading to the release of cytoplasmic contents. Recently, it has been reported that gasdermin D (GSDMD) mediates pyroptosis, which is cleaved and activated by caspase-1 and caspase-11 (24)(25)(26)(27).…”

mentioning

confidence: 99%

“…Its initiation depends on the activation of inflammatory caspases, such caspase-1, caspase-4, and caspase-5 in humans (23,24), leading to the release of cytoplasmic contents. Recently, it has been reported that gasdermin D (GSDMD) mediates pyroptosis, which is cleaved and activated by caspase-1 and caspase-11 (24)(25)(26)(27). The cleaved N-terminal fragment of GSDMD directly forms pores in the cytoplasmic membrane (28)(29)(30)(31)(32)(33).…”

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confidence: 99%

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Enterovirus 71 Inhibits Pyroptosis through Cleavage of Gasdermin D

Lei

Zhang

Xiao

et al. 2017

J Virol

110

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Enterovirus 71 (EV71) can cause hand-foot-and-mouth disease (HFMD) in young children. Severe infection with EV71 can lead to neurological complications and even death. However, the molecular basis of viral pathogenesis remains poorly understood. Here, we report that EV71 induces degradation of gasdermin D (GSDMD), an essential component of pyroptosis. Remarkably, the viral protease 3C directly targets GSDMD and induces its cleavage, which is dependent on the protease activity. Further analyses show that the Q193-G194 pair within GSDMD is the cleavage site of 3C. This cleavage produces a shorter N-terminal fragment spanning amino acids 1 to 193 (GSDMD ). However, unlike the N-terminal fragment produced by caspase-1 cleavage, this fragment fails to trigger cell death or inhibit EV71 replication. Importantly, a T239D or F240D substitution abrogates the activity of GSDMD consisting of amino acids 1 to 275 (GSDMD ). This is correlated with the lack of pyroptosis or inhibition of viral replication. These results reveal a previously unrecognized strategy for EV71 to evade the antiviral response.IMPORTANCE Recently, it has been reported that GSDMD plays a critical role in regulating lipopolysaccharide and NLRP3-mediated interleukin-1␤ (IL-1␤) secretion. In this process, the N-terminal domain of p30 released from GSDMD acts as an effector in cell pyroptosis. We show that EV71 infection downregulates GSDMD. EV71 3C cleaves GSDMD at the Q193-G194 pair, resulting in a truncated N-terminal fragment disrupted for inducing cell pyroptosis. Notably, GSDMD 1-275 (p30) inhibits EV71 replication whereas GSDMD 1-193 does not. These results reveal a new strategy for EV71 to evade the antiviral response. KEYWORDS EV71, HFMD, 3C, GSDMDE nterovirus 71 (EV71) is a major etiological agent of hand-foot-and-mouth disease (HFMD) which affects infants and children younger than 5 years of age. Most of these infections are self-limited with mild symptoms, including fever and vesicular eruptions mainly on the skin of hands and feet and in the mouth. However, some patients show severe neurological diseases, including aseptic meningitis, acute flaccid paralysis, encephalitis, and pulmonary edema. Since it was first isolated in California in 1974 (1-3), EV71 infection has caused many large-scale epidemics in the world, especially in the Asia-Pacific region (1, 4-6). To date, there are no effective therapeutic drugs for EV71 infection.EV71 belongs to the Enterovirus genus of the family Picornaviridae. The viral genome is approximately 7,500 nucleotides in length, with a single open reading frame that encodes a large precursor protein that is subsequently processed into three structural (VP0, VP1, and VP3) and seven nonstructural (2A, 2B, 2C, 3A, 3B, 3C, and 3D) proteins by the virus-encoded protease 2A or 3C (7). The three structural proteins and the RNA form provirions, in which VP0 is cleaved into VP2 and VP4 by RNA or 3CD, but the

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“…Recently, GSDMD has been identified as a key determinant of pyroptosis (24)(25)(26)(27). To investigate the impact of EV71 infection, we analyzed the expression of GSDMD.…”

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Enterovirus 71 Inhibits Pyroptosis through Cleavage of Gasdermin D

Lei

Zhang

Xiao

et al. 2017

J Virol

110

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“…MyD88 interacts with the death domain of IRAK4 and transmits the signal to the IL-1 receptor-associated kinase family, which triggers a phosphorylation cascade and activates NF-κB; then, the activated NF-κB is translocated into the nucleus and induces the expression of inflammatory genes and the release of a large number of inflammatory mediators [40]. Therefore, LPS can lead to the high expression of inflammatory factors via TLR4, and these highly expressed inflammatory factors can contribute to cell inflammatory death [41,42]. Furthermore, PDTC reduced the LPS-induced kidney injury of systemic lupus erythematosus-prone MRL/lpr mice by suppressing the NF-κB signaling pathway [43].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of NF-κB by Pyrrolidine Dithiocarbamate Prevents the Inflammatory Response in a Ligature-Induced Peri-Implantitis Model: A Canine Study

Jiang²,

Wang

et al. 2018

Cell Physiol Biochem

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Background/Aims: The roles of toll-like receptor 4 (TLR4) and nuclear factor-kappa B (NF-κB) in peri-implantitis are unclear. Here, we used a canine model of peri-implantitis to explore the effects of inhibiting NF-κB with pyrrolidine dithiocarbamate (PDTC) on the inflammatory response in ligature-induced peri-implantitis. Methods: After successfully establishing the peri-implantitis model, beagles were randomly assigned to normal, model or PDTC groups. ELISA tests were used to determine the levels of interleukin (IL)-1, IL-6, IL-8 and tumor necrosis factor alpha (TNF-α). Immunohistochemistry was employed to assess the expression of NF-κB p65. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed to determine the mRNA levels of TLR4 and NF-κB p65, and western blot analysis was used to measure the protein levels of TLR4 in periodontal tissues from each group. Periodontal ligament fibroblasts (PDLFs) were cultured and subsequently classified into PDLF normal, PDLF model, PDLF LPS, PDLF PDTC, and PDLF LPS + PDTC groups. An immunofluorescence assay was used to measure the expression level of NF-κB p65. The CCK-8 assay and flow cytometry were performed to evaluate cell proliferation and apoptosis. Results: The in vitro results indicated that NF-κB p65 and TLR4 were upregulated in canine periodontal tissues, and PDTC could suppress the expression levels of NF-κB p65 and TLR4. Inflammation could increase TLR4 protein expression in canine periodontal tissue, and PDTC could inhibit the inflammation-induced increase in TLR4 protein expression. These results revealed that PDTC could reverse the LPS-induced increases in the levels of IL-1, IL-6, IL-8 and TNF-α. In vivo, the results demonstrated that PDTC inhibited the LPS-induced NF-κB p65 upregulation, and PDTC could reverse the inhibitory effect of the PDLF model + LPS on the proliferation of periodontal fibroblasts. The results also showed that in the PDLF model, LPS promoted PDLF apoptosis by inducing implant periodontitis in canines, but PDTC inhibited the PDLF apoptosis and relieved implant periodontitis in canines. Conclusion: Based on our results, we concluded that PDTC can inhibit the expression of NF-κB and alleviate the inflammatory response induced by LPS, thereby preventing periodontal inflammation and reducing the development of peri-implantitis.

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“…Pyroptosis is initiated by the formation and activation of multi-protein complex inflammasomes. Recently identified Gasdermin D, a component of inflammasomes and a substrate of inflammatory caspases, is also required for pyroptosis [23,24].…”

Section: Other Types Of Programmed Necrosismentioning

confidence: 99%

The Implications of Several Forms of Programmed Necrosis for Cancer Therapy

Kim¹

2017

J Cancer Sci Ther

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The dogma that apoptosis and autophagy are the sole forms of Programmed Cell Death (PCD) is no longer accepted, due to the recent discovery of programmed necrosis, a non-apoptotic, non-autophagic form of PCD. Necroptosis, parthanatos, pyroptosis, and ferroptosis are all forms of programmed necrosis, as these types of cell death dismantle the cell in an ordered fashion that is distinctly different from apoptosis or autophagy. Several key cellular mediators and events in these types of PCD have been discovered. Here, we discuss the basic characteristics, molecular pathways, and possible implications of these lesser-known types of PCD in cancer treatment modalities such as chemotherapy and radiotherapy. Because resistance to apoptosis is often responsible for cancer treatment failures, novel therapeutic strategies that can activate alternative cell death programs have great appeal. Understanding the underlying mechanisms of these types of PCD may facilitate the development of diverse therapeutic strategies, particularly against apoptosis-resistant cancers.

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Pyroptosis: Gasdermin-Mediated Programmed Necrotic Cell Death

Cited by 1,993 publications

References 76 publications

Enterovirus 71 Inhibits Pyroptosis through Cleavage of Gasdermin D

Enterovirus 71 Inhibits Pyroptosis through Cleavage of Gasdermin D

Inhibition of NF-κB by Pyrrolidine Dithiocarbamate Prevents the Inflammatory Response in a Ligature-Induced Peri-Implantitis Model: A Canine Study

The Implications of Several Forms of Programmed Necrosis for Cancer Therapy

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