The 3a protein of severe acute respiratory syndrome-associated coronavirus induces apoptosis in Vero E6 cells

Law, Patrick Tik Wan; Wong, Chi Lok; Au, Thomas Chi Chuen; Chuck, Chi Pang; Kong, Siu Kai; Chan, Paul K.S.; To, Ka Fai; Lo, Anthony W.I.; Chan, Jimmy Yu Wai; Suen, Y. K.; Chan, Edwin; Fung, Kwok‐Pui; Waye, Mary Miu Yee; Sung, Joseph J.Y.; Lo, Y.M. Dennis; Tsui, Stephen Kwok‐Wing

doi:10.1099/vir.0.80813-0

Cited by 142 publications

(156 citation statements)

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“…Its overexpression alone is also sufficient to induce apoptosis in many cell types (Xiang et al, 2000). The tumour suppressor and transcription factor p53 can also enhance the proapoptotic activity of Bax, either by inducing its expression or by sequestrating Bcl-2 or Bcl-X L in the cytoplasm (Miyashita & Reed, 1995).We show here that, in addition to caspase-8 activation (Law et al, 2005), the SARS-CoV 3a protein also activates caspase-9 and other elements of the intrinsic pathway, including cytochrome c release, Bax oligomerization, p53 upregulation and p38 MAP kinase (MAPK) activation. We also show p38 MAPK activation to be important for the pro-apoptotic effects of the 3a protein.…”

mentioning

confidence: 72%

“…The 3a protein was shown to upregulate the expression of fibrinogen in A549 lung epithelial cells and to possess an ionchannel activity selective for monovalent cations (Lu et al, 2006). Ectopic expression of the 3a protein has been shown to induce apoptosis in Vero E6 cells through activation of caspase-8, chromatin condensation and DNA fragmentation (Law et al, 2005). In a Drosophila melanogaster expression system, it was also found to modulate cellular cytochrome c levels and caspase activity .…”

mentioning

confidence: 93%

“…We show here that, in addition to caspase-8 activation (Law et al, 2005), the SARS-CoV 3a protein also activates caspase-9 and other elements of the intrinsic pathway, including cytochrome c release, Bax oligomerization, p53 upregulation and p38 MAP kinase (MAPK) activation. We also show p38 MAPK activation to be important for the pro-apoptotic effects of the 3a protein.…”

Section: Introductionmentioning

confidence: 99%

“…In this system, there was increased caspase-8 activation, but no change in Bad or Bcl-2 levels, suggesting that the death-receptor (extrinsic) apoptosis pathway was activated (Law et al, 2005). We chose to study the apoptotic activity of the 3a protein in the Huh7 human hepatocellular carcinoma cell line, as liver cells have been shown to be permissive for SARS-CoV infection and replication (Kaye, 2006).…”

Section: Sars-cov 3a Protein Activates the Intrinsic Pathway Of Apoptmentioning

confidence: 99%

“…1b). As the 3a protein has been shown previously to activate caspase-8 (Law et al, 2005), we also checked for cleavage of Bid. Truncated Bid (tBid) has effects on the mitochondria and is important for cross-talk between the extrinsic and intrinsic pathways (Luo et al, 1998).…”

Section: Sars-cov 3a Protein Activates the Intrinsic Pathway Of Apoptmentioning

confidence: 99%

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Severe acute respiratory syndrome coronavirus 3a protein activates the mitochondrial death pathway through p38 MAP kinase activation

Padhan

Minakshi

Towheed

et al. 2008

Journal of General Virology

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The molecular mechanisms governing severe acute respiratory syndrome coronavirus-induced pathology are not fully understood. Virus infection and some individual viral proteins, including the 3a protein, induce apoptosis. However, the cellular targets leading to 3a protein-mediated apoptosis have not been fully characterized. This study showed that the 3a protein modulates the mitochondrial death pathway in two possible ways. Activation of caspase-8 through extrinsic signal(s) caused Bid activation. In the intrinsic pathway, there was activation of caspase-9 and cytochrome c release from the mitochondria. This was the result of increased Bax oligomerization and higher levels of p53 in 3a protein-expressing cells, which depended on the activation of p38 MAP kinase (MAPK) in these cells. For p38 activation and apoptosis induction, the 3a cytoplasmic domain was sufficient. In direct Annexin V staining assays, the 3a protein-expressing cells showed increased apoptosis that was attenuated with the p38 MAPK inhibitor SB203580. A block in nuclear translocation of the STAT3 transcription factor in cells expressing the 3a protein was also observed. These results have been used to present a model of 3a-mediated apoptosis. INTRODUCTIONThe aetiological agent for severe acute respiratory syndrome (SARS) was identified as a novel coronavirus (SARS-CoV) (Peiris et al., 2003). SARS-CoV has a polyadenylated, positive-sense RNA genome of approximately 30 kb (Marra et al., 2003). In addition to the prototypic coronavirus genes, the SARS-CoV genome also contains nine unique open reading frames (ORFs) (Marra et al., 2003). Of these, orf3a is the largest and encodes a protein of 274 aa, variously called ORF3A (Ito et al., 2005), X1 (Rota et al., 2003) or U274 (Tan et al., 2004b). The 3a protein has been predicted to contain an N-terminal signal peptide followed by three transmembrane domains and a C-terminal cytoplasmic domain of approximately 150 aa (Zeng et al., 2004).The 3a protein is associated with virus particles produced following infection of Vero E6 or Caco-2 cells (Ito et al., 2005;Shen et al., 2005) and can assemble into virus-like particles when co-expressed with the membrane and envelope proteins in insect cells (Shen et al., 2005). In vitro studies have also shown the 3a protein to interact with the viral envelope, membrane and spike proteins (Tan et al., 2004b;Tan, 2005) and the cellular protein caveolin-1 (Padhan et al., 2007). A deletion of orf3a was shown to reduce virus titres, but not to eliminate virus replication (Yount et al., 2005), and convalescent sera from SARS patients have antibodies to the 3a protein (Tan et al., 2004a), suggesting that it is expressed during virus infection of the host. The 3a protein was shown to upregulate the expression of fibrinogen in A549 lung epithelial cells and to possess an ionchannel activity selective for monovalent cations (Lu et al., 2006). Ectopic expression of the 3a protein has been shown to induce apoptosis in Vero E6 cells through activation of caspase-8, chromatin c...

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confidence: 72%

mentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Section: Sars-cov 3a Protein Activates the Intrinsic Pathway Of Apoptmentioning

confidence: 99%

Section: Sars-cov 3a Protein Activates the Intrinsic Pathway Of Apoptmentioning

confidence: 99%

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Severe acute respiratory syndrome coronavirus 3a protein activates the mitochondrial death pathway through p38 MAP kinase activation

Padhan

Minakshi

Towheed

et al. 2008

Journal of General Virology

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Subacute thyroiditis after SARS‐CoV‐2 infection

Semikov

Shulutko

Хоробрых

et al. 2021

Clinical Case Reports

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Evolution of SARS‐CoV‐2 genome from December 2019 to late March 2020: Emerged haplotypes and informative Tag nucleotide variations

Safari

InanlooRahatloo

Elahi

2020

Journal of Medical Virology

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SARS‐CoV‐2 causes serious disease in humans. First identified in November/December 2019 in China, it has rapidly spread world‐wide. We analyzed 2790 SARS‐CoV‐2 genome sequences from 56 countries that were available on April 2, 2020 to assess the evolution of the virus during this early phase of its expansion. We aimed to assess sequence variations that had evolved in virus genomes, giving greatest attention to the S gene. We also aimed to identify haplotypes that the variations may define and consider their geographic and chronologic distribution. Variations at 1930 positions that together cause 1203 amino acid changes were identified. The frequencies of changes normalized to lengths of genes and encoded proteins were relatively high in ORF3a and relatively low in M. A variation that causes an Asp614Gly near the receptor binding domain of S was found at high frequencies, and it was considered that this may contribute to the rapid spread of viruses with this variation. Our most important findings relate to haplotypes. Sixty‐six haplotypes that constitute thirteen haplotype groups (H1‐H13) were identified, and 84.6% of the 2790 sequences analyzed were associated with these haplotypes. The majority of the sequences (75.1%) were associated with haplotype groups H1‐H3. The distribution pattern of the haplotype groups differed in various geographic regions. A few were country/territory specific. Location and time of emergence of some haplotypes are discussed. Importantly, nucleotide variations that define the various haplotypes and Tag/signature variations for most of haplotypes are reported. The practical applications of these variations are discussed. This article is protected by copyright. All rights reserved.

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The 3a protein of severe acute respiratory syndrome-associated coronavirus induces apoptosis in Vero E6 cells

Cited by 142 publications

References 36 publications

Severe acute respiratory syndrome coronavirus 3a protein activates the mitochondrial death pathway through p38 MAP kinase activation

Severe acute respiratory syndrome coronavirus 3a protein activates the mitochondrial death pathway through p38 MAP kinase activation

Subacute thyroiditis after SARS‐CoV‐2 infection

Evolution of SARS‐CoV‐2 genome from December 2019 to late March 2020: Emerged haplotypes and informative Tag nucleotide variations

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