<scp>GSDMD</scp>
            membrane pore formation constitutes the mechanism of pyroptotic cell death

Sborgi, Lorenzo; Rühl, Sebastian; Mulvihill, Estefania; Pipercevic, Joka; Heilig, Rosalie; Stahlberg, Henning; Farady, Christopher J.; Müller, Daniel J.; Brož, Petr; Hiller, Sebastian

doi:10.15252/embj.201694696

Cited by 961 publications

(799 citation statements)

References 45 publications

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“…GSDMD 1-275 cleavage by caspase-1 induces pyroptosis by forming a large plasma membrane pore (28)(29)(30)(31)(32)(33). To evaluate the effect of EV71 3C on GSDMD, we assessed the cell viability and cell death of different cleavage fragments of GSDMD.…”

Section: Resultsmentioning

confidence: 99%

“…Upon activation by caspases, GSDMD undergoes proteolytic cleavage and releases its N-terminal domain, GSDMD 1-275 (28)(29)(30)(31)(32). As a result, this induces pyroptosis by causing extensive pore formation on the cell plasma membrane (28, 29, 31-33, 40, 41).…”

Section: Discussionmentioning

confidence: 99%

“…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). It is believed that pyroptosis can inhibit and clear intracellular pathogens (34).…”

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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

120

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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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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Enterovirus 71 Inhibits Pyroptosis through Cleavage of Gasdermin D

Lei

Zhang

Xiao

et al. 2017

J Virol

120

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“…Independently of cytokine maturation, caspase-1 is able to cleave gasdermin D [44,45]. The N-terminal segment of gasdermin D forms pores in membranes [46][47][48][49] and induces a type of cell death called pyroptosis. In contrast to the pyrin domainefficient activation of Dronc, which dissociates and cleaves its substrate Drice (Fig.…”

Section: The Role Of Asc In Cytokine Maturation and Pyroptosismentioning

confidence: 99%

The NLRC4 inflammasome: The pieces of the puzzle are falling into place

Hafner-Bratkovič¹

2017

Inflammasome

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Inflammasomes are intracellular multiprotein platforms for the activation of inflammatory caspases. As components of the innate immune system, they play an important role in the fight against microbes. However, aberrant inflammasome activation has been implicated in auto-inflammatory syndromes. This review focuses on the NLRC4 inflammasome. This is perhaps not the most extensively studied, yet its mechanism of activation is by far the best understood. The NLRC4 inflammasome is activated by several proteins originating from intracellular bacteria, which are first sensed by receptors of the NAIP family. Activated NAIP binds NLRC4, which further recruits dormant NLRC4 molecules in a prion-like oligomerization event. NLRC4 enables a strong amplification of the signal, providing a fast and robust host response. The review also discusses peculiar NLRC4 inflammasome functions in promoting eicosanoid biosynthesis, actin reorganization, and its roles in autoinflammatory syndromes and sterile inflammation. Finally, the first inflammasomeindependent engagement of NLRC4 in suppressing melanoma tumor growth is presented. The emerging roles of NLRC4 in various normal and pathological processes demonstrate that there is still plenty to be learned about the NLRC4 mechanism of activation and downstream functions.

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“…In addition, recent findings have provided evidence that the N-terminal domains of GSDMD and other gasdermin proteins (GSDMA and GSDMA3) are involved in pyroptotic pore formation. These pore-forming proteins can affect either plasmalemma or peroxisome and mitochondrial membranes (Ding et al, 2016;Sborgi et al, 2016).…”

Section: Pyroptosismentioning

confidence: 99%

Lysosomes in programmed cell death pathways: from initiators to amplifiers

Kavčič

Pegan

Turk

2016

Biological Chemistry

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Lysosome is the central organelle for intracellular degradation of biological macromolecules and organelles. The material destined for degradation enters the lysosomes primarily via endocytosis, autophagy and phagocytosis, and is degraded through the concerted action of more than 50 lysosomal hydrolases. However, lysosomes are also linked with numerous other processes, including cell death, inflammasome activation and immune response, as well as with lysosomal secretion and cholesterol recycling. Among them programmed cell death pathways including apoptosis have received major attention. In most of these pathways, cell death was accompanied by lysosomal membrane permeabilization and release of lysosomal constituents with an involvement of lysosomal hydrolases, including the cathepsins. However, it is less clear, whether lysosomal membrane permeabilization is really critical for the initiation of cell death programme(s). Therefore, the role of lysosomal membrane permeabilization in various programmed cell death pathways is reviewed, as well as the mechanisms leading to it.

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GSDMD membrane pore formation constitutes the mechanism of pyroptotic cell death

Cited by 961 publications

References 45 publications

Enterovirus 71 Inhibits Pyroptosis through Cleavage of Gasdermin D

Enterovirus 71 Inhibits Pyroptosis through Cleavage of Gasdermin D

The NLRC4 inflammasome: The pieces of the puzzle are falling into place

Lysosomes in programmed cell death pathways: from initiators to amplifiers

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