scholarly journals Zika virus infection induced apoptosis by modulating the recruitment and activation of pro-apoptotic protein Bax

2021 ◽  
Author(s):  
Xiaodong Han ◽  
Jiuqiang Wang ◽  
Yang Yang ◽  
Shuxiang Qu ◽  
Fang Wan ◽  
...  
Keyword(s):  
Zika Virus ◽  
Cell Apoptosis ◽  
Zikv Infection ◽  
Apoptotic Pathway ◽  
Subsequent Formation ◽  
Mitochondrial Apoptotic Pathway ◽  
Detailed Mechanism ◽  
Apoptotic Protein ◽  
Cyt C ◽  
Induced Apoptosis

Zika virus (ZIKV) infection is associated with microcephaly in newborns and serious neurological complications in adults. Apoptosis of neural progenitor cells induced by ZIKV infection is believed to be a main reason for ZIKV infection-related microcephaly. However, the detailed mechanism of ZIKV infection-induced apoptosis remains to be elucidated. In this report, ZIKV infection induced the conformational activation of the pro-apoptotic protein Bax, with subsequent formation of oligomers of Bax in the mitochondria. Cell apoptosis was reduced significantly in SY5Y cells subjected to Bax knockdown. Additionally, while decreasing Bax expression inhibited the release of Cyt c from the mitochondria and reduced the rate of loss of mitochondrial membrane potential induced by ZIKV infection, silencing Bak, caspase-8, and/or caspase-10 expression did not. Mitochondria isolated from the untreated ZIKV-infected cells displayed Bax-binding ability and the subsequent release of Cyt c. This study also indicated that the NS4B protein of ZIKV recruited Bax to the mitochondria and induced Bax conformational activation. The overexpressed NS4B was localized to the mitochondria and induced cell apoptosis by activating the pro-apoptotic protein Bax. All the above results indicated that ZIKV infection directly impacted the mitochondrial apoptotic pathway by modulating the recruitment and activation of Bax. Importance: Since the large outbreaks that occurred in the Pacific Islands and Latin America in 2013, Zika virus has been confirmed a neuroteratogenic pathogen and causative agent of microcephaly and other developmental anomalies of the central nervous system in children born to infected mothers. As the widespread apoptosis throughout the whole brain, studies in animal models have reinforced the link between microcephaly caused by ZIKV infection and NPC apoptosis. Currently, the detailed mechanism of ZIKV infection-induced apoptosis still remains to be elucidated. Here, we firstly demonstrate that ZIKV infection activated the classic signs of mitochondrial apoptotic pathway by modulating the recruitment and activation of Bax. ZIKV NS4B represents a novel viral apoptotic protein that can modulate the recruitment and activation of Bax and trigger the apoptotic program. This is a new insight into understanding the interplay between apoptosis and ZIKV infection.

scholarly journals Enterovirus 71 2B Induces Cell Apoptosis by Directly Inducing the Conformational Activation of the Proapoptotic Protein Bax

2016 ◽  
Vol 90 (21) ◽  
pp. 9862-9877 ◽  
Author(s):  
Haolong Cong ◽  
Ning Du ◽  
Yang Yang ◽  
Lei Song ◽  
Wenliang Zhang ◽  
...  
Keyword(s):  
Cell Apoptosis ◽  
Enterovirus 71 ◽  
Terminal Region ◽  
Ev71 Infection ◽  
Apoptotic Pathway ◽  
Hydrophobic Region ◽  
Mitochondrial Apoptotic Pathway ◽  
Proapoptotic Protein ◽  
2B Protein ◽  
Induced Apoptosis

ABSTRACTTo survive and replicate within a host, many viruses have evolved strategies that target crucial components within the apoptotic cascade, leading to either inhibition or induction of cell apoptosis. Enterovirus 71 (EV71) infections have been demonstrated to impact the mitochondrial apoptotic pathway and induce apoptosis in many cell lines. However, the detailed mechanism of EV71-induced apoptosis remains to be elucidated. In this study, we report that EV71 2B protein (2B) localized to the mitochondria and induced cell apoptosis by interacting directly with and activating the proapoptotic protein Bax. 2B recruited Bax to the mitochondria and induced Bax conformational activation. In addition, mitochondria isolated from 2B-expressing cells that were treated with a recombinant Bax showed increased Bax interaction and cytochromec(Cytc) release. Importantly, apoptosis in cells with either EV71 infection or 2B expression was dramatically reduced in Bax knockdown cells but not in Bak knockdown cells, suggesting that Bax played a pivotal role in EV71- or 2B-induced apoptosis. Further studies indicate that a hydrophobic region of 18 amino acids (aa) in the C-terminal region of 2B (aa 63 to 80) was responsible for the location of 2B in the mitochondria. A hydrophilic region of 14 aa in the N-terminal region of 2B was functional in Bax interaction and its subsequent activation. Moreover, overexpression of the antiapoptotic protein Bcl-XLabrogates 2B-induced release of Cytcand caspase activation. Therefore, this study provides direct evidence that EV71 2B induces cell apoptosis and impacts the mitochondrial apoptotic pathway by directly modulating the redistribution and activation of proapoptotic protein Bax.IMPORTANCEEV71 infections are usually accompanied by severe neurological complications. It has also been postulated that the induction of cell apoptosis resulting from tissue damage is a possible process of EV71-related pathogenesis. In this study, we report that EV71 2B protein (2B) localized to the mitochondria and induced cell apoptosis by interacting directly with and activating the proapoptotic protein Bax. This study provides evidence that EV71 induces cell apoptosis by modulating Bax activation and reveals important clues regarding the mechanism of Cytcrelease and mitochondrial permeabilization during EV71 infection.

scholarly journals CRISPR/Cas9 Knockout of Bak Mediates Bax Translocation to Mitochondria in response to TNFα/CHX-induced Apoptosis

2019 ◽  
Vol 2019 ◽  
pp. 1-8 ◽  
Author(s):  
Jingtian Zhang ◽  
Han Niu ◽  
Zhizhuang Joe Zhao ◽  
Xueqi Fu ◽  
Yuxiang Wang ◽  
...  
Keyword(s):  
Cell Line ◽  
Parp Cleavage ◽  
Caspase 8 ◽  
Caspase Activation ◽  
Apoptotic Pathway ◽  
Mitochondrial Apoptotic Pathway ◽  
Apoptotic Protein ◽  
Induced Apoptosis

TNFα/CHX-induced apoptosis is dependent on caspase-8 activation and regulated by Bcl-2. However, the specific participants and precise mechanisms underlying this apoptotic pathway are poorly understood. The proapoptotic proteins Bak and Bax—members of the Bcl-2 family—are essential for the functioning of the mitochondrial apoptotic pathway. In this study, we used the CRISPR/Cas9 system to knockout Bak in the human SH-SY5Y cell line and determined the effects of this knockout on TNFα/CHX-induced apoptosis. Our data showed that overexpression of Bcl-2 dramatically prevented TNFα/CHX-induced apoptosis, and then pro-apoptotic protein Bak was downregulated and became more resistant to TNFα/CHX-induced apoptosis, because both TNFα/CHX-induced PARP cleavage and caspase activation were blocked in BAK−/− cells or using specific siRNA, whereas Bax was dispensable in TNFα/CHX-induced apoptosis, as evidenced using specific siRNA. Bax translocated from the cytosol into the mitochondria in response to TNFα/CHX, and CRISPR/Cas9 knockout of Bak significantly decreased this translocation. These results indicate that TNFα/CHX-induced apoptosis does not occur in Bak−/− cells, suggesting that TNFα/CHX-induced apoptosis is Bak-dependent but Bax-independent.

Dexamethasone induces pancreatic β-cell apoptosis through upregulation of TRAIL death receptor

2021 ◽  
Author(s):  
Kanchana Suksri ◽  
Namoiy Semprasert ◽  
Mutita Junking ◽  
Suchanoot Kutpruek ◽  
Thawornchai Limjindaporn ◽  
...  
Keyword(s):  
Cell Apoptosis ◽  
Molecular Mechanisms ◽  
Cultured Cells ◽  
Death Receptor ◽  
Caspase 8 ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Apoptotic Protein ◽  
Induced Apoptosis ◽  
Trail Death Receptor

Long-term medication with dexamethasone (a synthetic glucocorticoid (GC) drug) results in hyperglycemia, or steroid-induced diabetes. Although recent studies revealed dexamethasone directly induces pancreatic β-cell apoptosis, its molecular mechanisms remain unclear. In our initial analysis of mRNA transcripts, we discovered the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathway may be involved in dexamethasone-induced pancreatic β-cell apoptosis. In the present study, a mechanism of dexamethasone-induced pancreatic β-cell apoptosis through the TRAIL pathway was investigated in cultured cells and isolated mouse islets. INS-1 cells were cultured with and without dexamethasone in the presence or absence of a glucocorticoid receptor (GR) inhibitor, RU486. We found that dexamethasone induced pancreatic β-cell apoptosis in association with the upregulation of TRAIL mRNA and protein expression. Moreover, dexamethasone upregulated the TRAIL death receptor (DR5) protein but suppressed the decoy receptor (DcR1) protein. Similar findings were observed in mouse isolated islets: dexamethasone increased TRAIL and DR5 compared to that of control mice. Furthermore, dexamethasone stimulated pro-apoptotic signaling including superoxide production, caspase-8, -9, and -3 activities, NF-B, and Bax, but repressed the anti-apoptotic protein, Bcl-2. All these effects were inhibited by the GR-inhibitor, RU486. Furthermore, knock down DR5 decreased dexamethasone-induced caspase 3 activity. Caspase-8 and caspase-9 inhibitors protected pancreatic β-cells from dexamethasone-induced apoptosis. Taken together, dexamethasone induced pancreatic β-cell apoptosis by binding to the GR and inducing DR5 and TRAIL pathway.

MicroRNA-15b enhances hypoxia/reoxygenation-induced apoptosis of cardiomyocytes via a mitochondrial apoptotic pathway

APOPTOSIS ◽  
2013 ◽  
Vol 19 (1) ◽  
pp. 19-29 ◽  
Author(s):  
Lifeng Liu ◽  
Guoming Zhang ◽  
Zhuo Liang ◽  
Xiuhua Liu ◽  
Tiande Li ◽  
...  
Keyword(s):  
Apoptotic Pathway ◽  
Mitochondrial Apoptotic Pathway ◽  
Induced Apoptosis ◽  
Hypoxia Reoxygenation

Ghrelin ameliorates A549 cell apoptosis caused by paraquat via p38-MAPK regulated mitochondrial apoptotic pathway

Toxicology ◽  
2019 ◽  
Vol 426 ◽  
pp. 152267 ◽  
Author(s):  
Shuqing Cui ◽  
Qing Nian ◽  
Gang Chen ◽  
Xingyong Wang ◽  
Jinying Zhang ◽  
...  
Keyword(s):  
P38 Mapk ◽  
A549 Cell ◽  
Cell Apoptosis ◽  
Apoptotic Pathway ◽  
Mitochondrial Apoptotic Pathway

Synthesis of 5-Alkynyltetrandrine Derivatives and Evaluation of their Anticancer Activity on A549 Cell Lines

2019 ◽  
Vol 19 (12) ◽  
pp. 1454-1462 ◽  
Author(s):  
Nana Niu ◽  
Tingli Qu ◽  
Jinfang Xu ◽  
Xiaolin Lu ◽  
Graham J. Bodwell ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Caspase 3 ◽  
Human Lung ◽  
A549 Cells ◽  
Human Lung Cancer ◽  
Coupling Reactions ◽  
Apoptotic Pathway ◽  
Future Design ◽  
Cyt C ◽  
Induced Apoptosis

Background: Lung cancer is one of the most prevalent malignancies and thus the development of novel therapeutic agents for managing lung cancer is imperative. Tetrandrine, a bis-benzyltetrahydroisoquinoline alkaloid isolated from Stephania tetrandra S. Moore, has been found to exert cytotoxic effects on cancerous cells. Methods: A series of 5-alkynyltetrandrine derivatives was synthesized via the Sonogashira cross-coupling reactions and evaluated as potential anti-tumor agents. The anti-tumor activities of 12 compounds on lung cancer cells (A549) were evaluated using the MTT method. The population of apoptotic cells was measured using a TUNEL assay. Real-time PCR quantified the gene expression levels of Bcl-2, Bax, survivin and caspase-3. The content of Cyt-C was detected using a Human Cyt-C ELISA kit. Results: Most of these compounds exhibited better activities than tetrandrine itself on A549 cells. Among them, compound 7 showed the highest cytotoxicity among the tested compounds against human lung adenocarcinoma A549 cells with an IC50 of 2.94 µM. Preliminary mechanistic studies indicated that compound 7 induced apoptosis of human lung cancer A549 cells and increased the level of the proapoptotic gene Bax, release of Cyt-C from mitochondria and activation of caspase-3 genes. Conclusion: The results suggest that compound 7 exerts its antitumor activity against A549 cells through the induction of the intrinsic (mitochondrial) apoptotic pathway. These findings will contribute to the future design of more effective anti-tumor agents in lung cancer therapy.

scholarly journals Human Fetal Astrocytes Infected with Zika Virus Exhibit Delayed Apoptosis and Resistance to Interferon: Implications for Persistence

Viruses ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 646 ◽  
Author(s):  
Daniel Limonta ◽  
Juan Jovel ◽  
Anil Kumar ◽  
Adriana Airo ◽  
Shangmei Hou ◽  
...  
Keyword(s):  
Zika Virus ◽  
Chronic Infection ◽  
Fetal Brain ◽  
Antiviral Response ◽  
Zikv Infection ◽  
Persistently Infected ◽  
Adaptive Mutations ◽  
Viral Shedding ◽  
Brain Infection ◽  
Induced Apoptosis

Zika virus (ZIKV) infection and persistence during pregnancy can lead to microcephaly and other fetal neurological disorders collectively known as Congenital Zika Syndrome. The immunological and virological events that contribute to the establishment of persistent ZIKV infection in humans are unclear though. Here we show that human fetal astrocytes (HFAs), the most abundant cell type in the central nervous system, become persistently infected with ZIKV resulting in continuous viral shedding for at least one month; a process that is facilitated by TIM/TAM receptors. HFAs are relatively resistant to ZIKV-induced apoptosis, a factor that may be important for chronic infection of these cells. Once infection was established, interferon treatment did not reduce virus replication. Moreover, the fact that the innate immune system was highly activated in persistently infected HFAs indicates that the virus can thrive in the presence of a sustained antiviral response. RNAseq analyses of persistently infected cells revealed that ZIKV alters host gene expression in a manner that could affect developmental processes. Conversely, data from sequencing of ZIKV genomes in persistently infected HFAs suggest that adaptive mutations were not required for establishing chronic infection. Based on these results, we postulate that HFAs are reservoirs for ZIKV in the fetal brain and that moderate apoptosis combined with inefficient antiviral response from these cells may contribute to the establishment of chronic brain infection associated with the ZIKV neurodevelopmental abnormalities.

Sign in / Sign up

Export Citation Format

Share Document