Caspase-8 is the molecular switch for apoptosis, necroptosis and pyroptosis

Fritsch, Melanie; Günther, Saskia Diana; Schwarzer, Robin; Albert, Marie‐Christine; Schorn, Fabian; Werthenbach, Jan Paul; Schiffmann, Leif; Stair, Neil Richard; Stocks, Hannah; Seeger, Jens M.; Lamkanfi, Mohamed; Krönke, Martin; Pasparakis, Manolis; Kashkar, Hamid

doi:10.1038/s41586-019-1770-6

Cited by 625 publications

(496 citation statements)

References 157 publications

Supporting

Mentioning

477

Contrasting

Unclassified

Order By: Relevance

“…Interestingly, the interaction between the ASC speck and caspase‐8 was found to be mediated by the PYD (pyrin domain) of ASC and the DED (death effector domain) of caspase‐8, unlike for caspase‐1 which is recruited by the ASC CARD 149,150 . Conversely, the interaction between ASC and caspase‐8 can go both ways, in which caspase‐8 initiates receptor‐independent ASC speck formation, and subsequent caspase‐1‐dependent pyroptosis as recently proposed by several studies 151,152 . Collectively, the unusual link between ASC and caspase‐8 might serve as a back‐up pathway in the case of pathogen‐induced inactivation of the protease activity of caspase‐1 or caspase‐8, respectively.…”

Section: Cross Talkmentioning

confidence: 81%

Cross talk between intracellular pathogens and cell death

Demarco

Chen

Brož

2020

Immunological Reviews

View full text Add to dashboard Cite

Infections with bacterial pathogens often results in the initiation of programmed cell death as part of the host innate immune defense, or as a bacterial virulence strategy. Induction of host cell death is controlled by an elaborate network of innate immune and cell death signaling pathways and manifests in different morphologically and functionally distinct forms of death, such as apoptosis, necroptosis, NETosis and pyroptosis. The mechanism by which host cell death restricts bacterial replication is highly cell‐type and context depended, but its physiological importance is highlighted the diversity of strategies bacterial pathogens use to avoid induction of cell death or to block cell death signaling pathways. In this review, we discuss the latest insights into how bacterial pathogens elicit and manipulate cell death signaling, how different forms of cell death kill or restrict bacteria and how cell death and innate immune pathway cross talk to guard against pathogen‐induced inhibition of host cell death.

show abstract

Section: Cross Talkmentioning

confidence: 81%

Cross talk between intracellular pathogens and cell death

Demarco

Chen

Brož

2020

Immunological Reviews

View full text Add to dashboard Cite

show abstract

“…Caspase-1 can induce apoptosis in GSDMD-deficient cells (21). Caspase-8 is a switch molecule for apoptosis, pyroptosis and necroptosis (22). It is commonly known that the continuous expression of p53 leads to the initiation of apoptosis after treatment with cytotoxic antitumor agents (23).…”

Section: Discussionmentioning

confidence: 99%

Distinct characteristics of dasatinib‑induced pyroptosis in gasdermin E‑expressing human lung cancer A549 cells and neuroblastoma SH‑SY5Y cells

Zhang

Chen

2020

Oncol Lett

View full text Add to dashboard Cite

Dasatinib, a multikinase inhibitor, is used in the treatment of chronic myeloid leukemia and was developed to overcome imatinib resistance. Its mechanism of action involves the induction of apoptosis, autophagy and necroptosis. However, it remains unclear whether dasatinib can induce pyroptosis. In the present study, gasdermin E (GSDME)-expressing SH-SY5Y and A549 cells were chosen for investigation. Typical pyroptotic features, such as cleavage of GSDME protein, leakage of lactate dehydrogenase and large bubbled morphology, were observed in both cell lines after exposure to dasatinib. The generation of GSDME fragments was inhibited by specific caspase-3 inhibitor zDEVD in SH-SY5Y cells and pan-caspase inhibitor zVAD in A549 cells. Moreover, distinct characteristics of pyroptosis were observed in A549 cells, which occurred only with a high percentage of Annexin V/propidium iodide double-stained cells and low level of GSDME protein cleavage. The sensitivity of A549 cells to dasatinib is significantly reduced by increasing cell numbers. The elevation of GSDMD and GSDME protein levels was induced by low concentrations of dasatinib, which was not influenced by the reduction of p53 protein with RNA interference. In conclusion, to the best of our knowledge, this is the first study to report that dasatinib can induce pyroptosis in tumor cells and increase the protein levels of GSDMD and GSDME in a p53-independent manner.

show abstract

“…IL-6, promptly and transiently produced in response to infections and tissue injuries, contributes to host defense through the stimulation of acute phase responses, hematopoiesis, in ammatory and immune reactions [58,59]. Caspase-8 is the initiator caspase of extrinsic apoptosis and required for the activation of NF-κB and secretion of cytokines in response to activated antigen receptors [60]. Quercetin, kaempferol, luteolin and naringenin, all can inhibit the activation of MAPK and RELA, decrease the expression of IL-6 and CASP8 [61][62][63][64][65].…”

Section: Discussionmentioning

confidence: 99%

Exploring the Mechanisms of Lian Hua Qing Wen Capsule against COVID-19 by Network Pharmacology and Molecular Docking Approach

Chen¹,

Qu²,

Tan³

et al. 2020

Preprint

View full text Add to dashboard Cite

Background The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 or COVID-19) disease has led to a wide-spread global pandemic. There is no specific antiviral drug proven effective for the treatment of patients with COVID-19 at present. Combination of western and traditional Chinese medicine (TCM) is recommended, and Lian Hua Qing Wen (LHQW) capsule is a basic prescription and widely used to treat COVID-19 in China. However, the mechanisms of LHQW capsule treating COVID-19 are not clear. The aim of the study is to explore the mechanisms of LHQW capsule treating COVID-19 based on network pharmacy and molecular docking approach. Methods The active compounds and targets of LHQW capsule were obtained from traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP). COVID-19 related target genes were obtained from GeneCards database and OMIM database. Protein–protein interaction (PPI) networks of LHQW capsule targets and COVID-19-related genes were visualized and merged to identify the candidate targets for LHQW capsule treating COVID-19. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were also performed. The hub genes involved in the gene-related pathways were screened and their corresponding compounds were used for in vitro validation of molecular docking predictions.Results A total of 185 active compounds of LHQW capsule were screened out, and 263 targets were predicted. Third hundred and fifty-two COVID-19 related target genes were obtained from GeneCards database and OMIM database. GO functional enrichment analysis showed that the biological processes of LHQW capsule treating COVID-19 were closely linked with the regulation of inflammation, immunity, cytokines production, vascular permeability, oxidative stress and apoptosis. KEGG enrichment analysis revealed that the pathways of LHQW capsule treating COVID-19 were significantly enriched in AGE−RAGE signaling pathway in diabetic complications, Kaposi sarcoma−associated herpesvirus infection, TNF, IL−17, and Toll−like receptor (TLR) signaling pathway. The hub targets genes in the gene-related pathways analysis of LHQW capsule treating COVID-19 included MAPK1, MAPK3, RELA, IL-6 and CASP8, which closely associated with inflammation, cytokines storm and apoptosis. Finally, molecular docking showed that top 5 compounds of LHQW capsule also had good binding activities to the important targets in COVID-19.Conclusions The mechanisms of LHQW capsule treating COVID-19 may involve in inhibiting inflammatory response, cytokine storm and virus infection, and regulating immune reactions, apoptosis and endothelial barrier.

show abstract

Caspase-8 is the molecular switch for apoptosis, necroptosis and pyroptosis

Cited by 625 publications

References 157 publications

Cross talk between intracellular pathogens and cell death

Cross talk between intracellular pathogens and cell death

Distinct characteristics of dasatinib‑induced pyroptosis in gasdermin E‑expressing human lung cancer A549 cells and neuroblastoma SH‑SY5Y cells

Exploring the Mechanisms of Lian Hua Qing Wen Capsule against COVID-19 by Network Pharmacology and Molecular Docking Approach

Contact Info

Product

Resources

About