Replication of a Cytopathic Strain of Bovine Viral Diarrhea Virus Activates PERK and Induces Endoplasmic Reticulum Stress-Mediated Apoptosis of MDBK Cells

Jordan, Robert; Wang, Limin; Graczyk, Thomas M.; Block, Timothy M.; Romano, Patrick R.

doi:10.1128/jvi.76.19.9588-9599.2002

Cited by 164 publications

(146 citation statements)

References 57 publications

(86 reference statements)

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“…Although the NS3/ NS3∆50 protein induces caspase-8-and -9-dependent apoptosis, several lines of evidence suggest that several factors (cellular and/or viral) or activation pathways of apoptosis are likely to be involved in the BVDV-associated apoptosis process. The facts that oxidative stress is observed in cells infected with cp BVDV [40], and that caspase-12-associated ER stress, a feature that was not addressed in this study, is observed in cp BVDV-induced apoptosis are consistent with the latter statement [18]. Caspase-12, which resides within the cytoplasmic side of the ER, is believed to play a central role in the ER stress-mediated apoptosis [31] and can activate caspase-8 [7] which in turn stimulates, through Bid processing, cytochrome c release and activates caspase-9 [17].…”

Section: Discussionsupporting

confidence: 85%

“…In addition, oxydative stress [40], intracellular viral RNA accumulation [44], caspase-12-associated ER stress [18], and mitochondriadependent caspase-9 activation [11] have been reported to be associated with cp BVDV-induced apoptosis. Here we show that NS3/NS3∆50 of BVDV induced apoptosis, and correlated with both caspase-8 and caspase-9 activation.…”

Section: Discussionmentioning

confidence: 99%

“…This apoptosis process has been associated with the accumulation of large amounts of viral RNA [44], cleavage of poly(ADP-ribose) polymerase (PARP) [14], mitochondrial-dependent caspase-9 activation [11], and endoplasmic reticulum (ER) stress induction that correlates with the activation of caspase-12 [18]. It is prevented by certain anti-oxidants [40].…”

Section: Introductionmentioning

confidence: 99%

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The bovine viral diarrhea virus (BVDV) NS3 protein, when expressed alone in mammalian cells, induces apoptosis which correlates with caspase-8 and caspase-9 activation

2005

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-The bovine viral diarrhea virus (BVDV) strains exist as two biotypes, cytopathic (cp) and noncytopathic (ncp), according to their effects on tissue culture cells. It has been previously reported that cell death associated to cp BVDV in vitro is mediated by apoptosis. Here, experiments were conducted to determine the involvement of the NS3 protein in the induction of apoptosis. The NS3-and NS3∆50 (deleted from the NH2-terminal 50 amino acids)-cDNA encoding sequences of BVDV NADL cp reference strain were cloned into adenoviral vectors (AdV) from which the BVDV gene of interest could be expressed from a tetracycline-responsive promoter. A549tTA cells infected in vitro with NS3 or NS3∆50-expressing AdV showed cytopathic changes characterized by cell rounding and detachment, and nucleus chromatin condensation. DNA fragmentation assays, cytochrome c release, and activation of cellular caspases performed on these infected cells clearly correlated with the observed cytopathic changes with apoptosis. The BVDV NS3∆50-induced apoptotic process was inhibited by caspase-8-and -9-specific peptide inhibitors (Z-IETD-FMK and Z-LEHD-FMK). Furthermore, apoptosis was inhibited in cells expressing the R1 subunit of herpes simplex virus type 2 ribonucleotide reductase (HSV2-R1) or hsp70, two proteins which are known to inhibit apoptosis associated with caspase-8 activation and cytochrome c release-dependent caspase-9 activation, respectively. Given that HSV2-R1, a specific inhibitor of the caspase-8 activation pathway, efficiently suppressed apoptosis and also prevented caspase-9 activation, the overall results indicate that the BVDV NS3/NS3∆50 induces apoptosis initiated by caspase-8 activation and subsequent cytochrome c release-dependent caspase-9 activation. bovine viral diarrhea virus / NS3 protein / apoptosis / caspases

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The bovine viral diarrhea virus (BVDV) NS3 protein, when expressed alone in mammalian cells, induces apoptosis which correlates with caspase-8 and caspase-9 activation

2005

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“…It is also known that UPR can activate proapoptotic gene expression (such as that of GADD153), which in turn can induce infected cells to undergo apoptosis (23,33,61). Expression levels of GADD153 were increased only in rSV5V⌬C-infected cells (consistent with the induction of apoptosis seen in rSV5V⌬C-infected cells).…”

Section: Discussionmentioning

confidence: 57%

Conserved Cysteine-Rich Domain of Paramyxovirus Simian Virus 5 V Protein Plays an Important Role in Blocking Apoptosis

Sun¹,

Rothermel²,

Shuman³

et al. 2004

J Virol

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The paramyxovirus family includes many well-known human and animal pathogens as well as emerging viruses such as Hendra virus and Nipah virus. The V protein of simian virus 5 (SV5), a prototype of the paramyxoviruses, contains a cysteine-rich C-terminal domain which is conserved among all paramyxovirus V proteins. The V protein can block both interferon (IFN) signaling by causing degradation of STAT1 and IFN production by blocking IRF-3 nuclear import. Previously, it was reported that recombinant SV5 lacking the C terminus of the V protein (rSV5V⌬C) induces a severe cytopathic effect (CPE) in tissue culture whereas wild-type (wt) SV5 infection does not induce CPE. In this study, the nature of the CPE and the mechanism of the induction of CPE were investigated. Through the use of DNA fragmentation, terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling, and propidium iodide staining assays, it was shown that rSV5V⌬C induced apoptosis. Expression of wt V protein prevented apoptosis induced by rSV5V⌬C, suggesting that the V protein has an antiapoptotic function. Interestingly, rSV5V⌬C induced apoptosis in U3A cells (a STAT1-deficient cell line) and in the presence of neutralizing antibody against IFN, suggesting that the induction of apoptosis by rSV5V⌬C was independent of IFN and IFN-signaling pathways. Apoptosis induced by rSV5V⌬C was blocked by a general caspase inhibitor, Z-VAD-FMK, but not by specific inhibitors against caspases 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 13, suggesting that rSV5V⌬C-induced apoptosis can occur in a caspase 12-dependent manner. Endoplasmic reticulum stress can lead to activation of caspase 12; compared to the results seen with mock and wt SV5 infection, rSV5V⌬C infection induced ER stress, as demonstrated by increased expression levels of known ER stress indicators GRP 78, GRP 94, and GADD153. These data suggest that rSV5V⌬C can trigger cell death by inducing ER stress.

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“…Similarly to proteasomal inhibition, unchecked viral replication in malignant cells leads to an accumulation of viral proteins. Several reports have highlighted the importance of ER stress in the response to viral infection (Jordan et al, 2002;Su et al, 2002). The ER is essential for the folding and posttranslational modification of viral proteins.…”

Section: Discussionmentioning

confidence: 99%

Reovirus therapy stimulates endoplasmic reticular stress, NOXA induction, and augments bortezomib-mediated apoptosis in multiple myeloma

et al. 2011

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Oncolytic virotherapy with reovirus has demonstrated anti-cancer activity and minimal toxicity in clinical trials, but the mechanisms underlying these effects have not been fully elucidated. Reolysin, a proprietary formulation of reovirus for cancer therapy, stimulated selective viral replication and apoptosis in multiple myeloma (MM) cells. Reolysin-mediated apoptosis was associated with an induction of endoplasmic reticular (ER) stress-related gene expression, swelling of the endoplasmic reticulum, increases in intracellular calcium levels and a strong induction of the Bcl-2 homology 3 (BH3)-only pro-apoptotic protein NOXA. Knockdown of NOXA expression by short hairpin RNA significantly reduced the pro-apoptotic effects of Reolysin. We next showed that co-administration of Reolysin and bortezomib resulted in the dual accumulation of viral and ubiquitinated proteins, which led to enhanced ER stress, NOXA induction and apoptosis. Importantly, the combination of reovirus infection and proteasomal inhibition significantly decreased tumor burden in a xenograft and syngeneic bone disease model of MM without exhibiting adverse side effects. Our study establishes ER stress stimulation and NOXA induction as novel mediators of reovirus-induced apoptosis. Furthermore, reovirus infection can be used as a promising approach to augment the anti-myeloma activity of bortezomib by promoting additional stress to the endoplasmic reticulum of MM cells.

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Replication of a Cytopathic Strain of Bovine Viral Diarrhea Virus Activates PERK and Induces Endoplasmic Reticulum Stress-Mediated Apoptosis of MDBK Cells

Cited by 164 publications

References 57 publications

The bovine viral diarrhea virus (BVDV) NS3 protein, when expressed alone in mammalian cells, induces apoptosis which correlates with caspase-8 and caspase-9 activation

The bovine viral diarrhea virus (BVDV) NS3 protein, when expressed alone in mammalian cells, induces apoptosis which correlates with caspase-8 and caspase-9 activation

Conserved Cysteine-Rich Domain of Paramyxovirus Simian Virus 5 V Protein Plays an Important Role in Blocking Apoptosis

Reovirus therapy stimulates endoplasmic reticular stress, NOXA induction, and augments bortezomib-mediated apoptosis in multiple myeloma

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