NLRP3 regulates a non-canonical platform for caspase-8 activation during epithelial cell apoptosis

Chung, Hyunsoo; Vilaysane, Akosua; Lau, Arthur; Ståhl, Martin; Morampudi, Vijay; Bondzi-Simpson, Adom; Platnich, Jaye M.; Bracey, NA; French, MC; Beck, PL; Chun, Justin; Vallance, Bruce A.; Muruve, DA

doi:10.1038/cdd.2016.14

Cited by 90 publications

(85 citation statements)

References 43 publications

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“…Alternatively, perhaps the HCV-induced apoptotic and pyroptotic pathways share a common origin that activates both of them. Interestingly, recent evidence suggests that in addition to their classical role in activating caspase-1 and inducing pyroptosis, NLRP3 inflammasomes can also activate caspase-8, which in turn induces apoptosis6970717273. This could be the case in HCV infection whereby activation of the NLRP3 inflammasome activates caspase-8 and caspase-1 to induce both apoptosis and pyroptosis, respectively.…”

Section: Discussionmentioning

confidence: 99%

Hepatitis C Virus Infection of Cultured Human Hepatoma Cells Causes Apoptosis and Pyroptosis in Both Infected and Bystander Cells

Kofahi

Taylor

Hirasawa

et al. 2016

Sci Rep

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Individuals infected with hepatitis C virus (HCV) are at high risk of developing progressive liver disease, including cirrhosis and hepatocellular carcinoma (HCC). How HCV infection causes liver destruction has been of significant interest for many years, and apoptosis has been proposed as one operative mechanism. In this study, we employed a tissue culture-adapted strain of HCV (JFH1T) to test effects of HCV infection on induction of programmed cell death (PCD) in Huh-7.5 cells. We found that HCV infection reduced the proliferation rate and induced caspase-3-mediated apoptosis in the infected cell population. However, in addition to apoptosis, we also observed infected cells undergoing caspase-1-mediated pyroptosis, which was induced by NLRP3 inflammasome activation. By co-culturing HCV-infected Huh-7.5 cells with an HCV-non-permissive cell line, we also demonstrated induction of both apoptosis and pyroptosis in uninfected cells. Bystander apoptosis, but not bystander pyroptosis, required cell-cell contact between infected and bystander cells. In summary, these findings provide new information on mechanisms of cell death in response to HCV infection. The observation that both apoptosis and pyroptosis can be induced in bystander cells extends our understanding of HCV-induced pathogenesis in the liver.

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Section: Discussionmentioning

confidence: 99%

Hepatitis C Virus Infection of Cultured Human Hepatoma Cells Causes Apoptosis and Pyroptosis in Both Infected and Bystander Cells

Kofahi

Taylor

Hirasawa

et al. 2016

Sci Rep

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“…ASC has been reported to trigger Fas ligand-induced caspase-8-dependent apoptosis [30, 31], but reports on ASC and caspase-9 are few. McConnell et al [32] demonstrated that ASC (TMS1)-induced apoptosis proceeded through a CARD-dependent aggregation step followed by the activation of a caspase-9-mediated pathway.…”

Section: Discussionmentioning

confidence: 99%

ASC Induces Apoptosis via Activation of Caspase-9 by Enhancing Gap Junction-Mediated Intercellular Communication

Kitazawa¹,

Hida²,

Fujii³

et al. 2017

PLoS ONE

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ASC (apoptosis-associated speck-like protein containing a CARD) is a key adaptor molecule of inflammasomes that mediates inflammatory and apoptotic signals. Aberrant methylation-induced silencing of ASC has been observed in a variety of cancer cells, thus implicating ASC in tumor suppression, although this role remains incompletely defined especially in the context of closely neighboring cell proliferation. As ASC has been confirmed to be silenced by abnormal methylation in HT1080 fibrosarcoma cells as well, this cell line was investigated to characterize the precise role and mechanism of ASC in tumor progression. The effects of ASC were examined using in vitro cell cultures based on comparisons between low and high cell density conditions as well as in a xenograft murine model. ASC overexpression was established by insertion of the ASC gene into pcDNA3 and pMX-IRES-GFP vectors, the latter being packed into a retrovirus and subjected to reproducible competitive assays using parental cells as an internal control, for evaluation of cell viability. p21 and p53 were silenced using shRNA. Cell viability was suppressed in ASC-expressing transfectants as compared with control cells at high cell density conditions in in vitro culture and colony formation assays and in in vivo ectopic tumor formation trials. This suppression was not detected in low cell density conditions. Furthermore, remarkable progression of apoptosis was observed in ASC-introduced cells at a high cell density, but not at a low one. ASC-dependent apoptosis was mediated not by p21, p53, or caspase-1, but rather by cleavage of caspase-9 as well as by suppression of the NF-κB-related X-linked inhibitor-of-apoptosis protein. Caspase-9 cleavage was observed to be dependent on gap junction formation. The remarkable effect of ASC on the induction of apoptosis through caspase-9 and gap junctions revealed in this study may lead to promising new approaches in anticancer therapy.

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“…Caspase-8-mediated apoptosis is activated by the NLRC4 inflammasome through the interaction of SUG1 and FADD (95) and complex formation of NLRP3-ASC on mitochondria can activate caspase-8 in epithelial cells (96). In absence of caspase-1 in dendritic cells (97) or macrophages (98) inflammasomes can induce apoptosis, but in presence of caspase-1 and -11 inflammasomes can engage another form of programmed necrotic cell death; pyroptosis.…”

Section: Caspase-8 In Inflammasomesmentioning

confidence: 99%

Caspase‐8: regulating life and death

Tummers

Green

2017

Immunological Reviews

577

421

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Summary Roles for cell death in development, homeostasis, and the control of infections and cancer have long been recognized. Whereas excessive cell damage results in passive necrosis, cells can be triggered to engage molecular programs that result in cell death. Such triggers include cellular stress, oncogenic signals that engage tumor suppressor mechanisms, pathogen insults, and immune mechanisms. The best-known forms of programmed cell death are apoptosis and a recently recognized regulated necrosis termed necroptosis. Of the two best understood pathways of apoptosis, the extrinsic and intrinsic (mitochondrial) pathways, the former is induced by the ligation of death receptors, a subset of the TNF receptor (TNFR) superfamily. Ligation of these death receptors can also induce necroptosis. The extrinsic apoptosis and necroptosis pathways regulate each other and their balance determines whether cells live. Integral in the regulation and initiation of death receptor-mediatedactivation of programmed cell death is the aspartate-specific cysteine protease (caspase)-8. This review describes the role of caspase-8 in the initiation of extrinsic apoptosis execution and the mechanism by which caspase-8 inhibits necroptosis. The importance of caspase-8 in development and homeostasis and the way that dysfunctional caspase-8 may contribute to the development of malignancies in mice and humans are also explored.

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NLRP3 regulates a non-canonical platform for caspase-8 activation during epithelial cell apoptosis

Cited by 90 publications

References 43 publications

Hepatitis C Virus Infection of Cultured Human Hepatoma Cells Causes Apoptosis and Pyroptosis in Both Infected and Bystander Cells

Hepatitis C Virus Infection of Cultured Human Hepatoma Cells Causes Apoptosis and Pyroptosis in Both Infected and Bystander Cells

ASC Induces Apoptosis via Activation of Caspase-9 by Enhancing Gap Junction-Mediated Intercellular Communication

Caspase‐8: regulating life and death

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