Reduced steady-state levels of vaccinia virus-specific early mRNAs in interferon-treated chick embryo fibroblasts

Grün, Joachim R.; Kroon, Erna Geessien; Zöller, Barbara; Krempien, U.; Jungwirth, C.

doi:10.1016/0042-6822(87)90234-0

Cited by 12 publications

(5 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The inhibition of encephalomyocarditis virus (EMCV) replication seems to correlate with 2-5A synthetase induction . Likewise, mengovirus and vaccinia replication inhibitions were characterized by high 2-5A synthetase levels (Chebath et al, 198713;Grun et al, 1987). Resistance to ve-sicular stomatitis virus (VSV) replication, however, can occur in the absence of a detectable increase in 2-5A synthetase activity (Hovanessian et al, 1981b;Meurs et al, 1981).…”

Section: Mmt P-monomethoxytritylmentioning

confidence: 99%

The 2–5 A system: Modulation of viral and cellular processes through acceleration of RNA degradation

Player

Torrence

1998

Pharmacology & Therapeutics

245

195

View full text Add to dashboard Cite

The 2-5A system is an RNA degradation pathway that can be induced by the interferons (IFNs). Treatment of cells with IFN activates genes encoding several double-stranded RNA (dsRNA)-dependent synthetases. These enzymes generate 5'-triphosphorylated, 2',5'-phosphodiester-linked oligoadenylates (2-5A) from ATP. The effects of 2-5A in cells are transient since 2-5A is unstable in cells due to the activities of phosphodiesterase and phosphatase. 2-5A activates the endoribonuclease 2-5A-dependent RNase L, causing degradation of single-stranded RNA with moderate specificity. The human 2-5A-dependent RNase is an 83.5 kDa polypeptide that has little, if any, RNase activity, unless 2-5A is present. 2-5A binding to RNase L switches the enzyme from its off-state to its on-state. At least three 2',5'-linked oligoadenylates and a single 5'-phosphoryl group are required for maximal activation of the RNase. Even though the constitutive presence of 2-5A-dependent RNase is observed in nearly all mammalian cell types, cellular amounts of 2-5A-dependent mRNA and activity can increase after IFN treatment. One well-established role of the 2-5A system is as a host defense against some types of viruses. Since virus infection of cells results in the production and secretion of IFNs, and since dsRNA is both a frequent product of virus infection and an activator of 2-5A synthesis, the replication of encephalomyocarditis virus, which produces dsRNA during its life cycle, is greatly suppressed in IFN-treated cells as a direct result of RNA decay by the activated 2-5A-dependent RNase. This review covers the organic chemistry, enzymology, and molecular biology of 2-5A and its associated enzymes. Additional possible biological roles of the 2-5A system, such as in cell growth and differentiation, human immunodeficiency virus replication, heat shock, atherosclerotic plaque, pathogenesis of Type I diabetes, and apoptosis, are presented.

show abstract

Section: Mmt P-monomethoxytritylmentioning

confidence: 99%

The 2–5 A system: Modulation of viral and cellular processes through acceleration of RNA degradation

Player

Torrence

1998

Pharmacology & Therapeutics

245

195

View full text Add to dashboard Cite

show abstract

“…Specifically, VSV replication in CEF is very sensitive to chicken IFN, and therefore this virus is currently used to measure the antiviral activity of IFN preparations (37,(50)(51)(52). Vaccinia virus replication in CEF is inhibited by chicken IFN by posttranscriptional mechanisms (17,23,24). The results of our experiments, shown in Fig.…”

Section: Resultsmentioning

confidence: 72%

“…The inhibition of viral protein synthesis observed in rcIFN-treated cells infected with VSV and vaccinia virus suggests that replication of these viruses is being affected at a translational or a pretranslational step. In the case of vaccinia virus, inhibition of early viral protein synthesis and degradation of early viral mRNAs have been shown to occur in IFN-treated CEF (13,17,24), suggesting that the activities of both PKR and 2-5A synthetase play an important role in the IFN-sensitive phenotype of this virus in chicken cells. In most cell lines tested, vaccinia virus has been reported to be resistant to IFN (66), and this resistance has been associated with the activity of two "anti-antiviral" proteins encoded by the virus.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Possible Involvement of the Double-Stranded RNA-Binding Core Protein ςA in the Resistance of Avian Reovirus to Interferon

Martı́nez-Costas

Lopez

Vakharia

et al. 2000

J Virol

View full text Add to dashboard Cite

Treatment of primary cultures of chicken embryo fibroblasts with a recombinant chicken alpha/beta interferon (rcIFN) induces an antiviral state that causes a strong inhibition of vaccinia virus and vesicular stomatitis virus replication but has no effect on avian reovirus S1133 replication. The fact that avian reovirus polypeptides are synthesized normally in rcIFN-treated cells prompted us to investigate whether this virus expresses factors that interfere with the activation and/or the activity of the IFN-induced, double-stranded RNA (dsRNA)-dependent enzymes. Our results demonstrate that extracts of avian-reovirus-infected cells, but not those of uninfected cells, are able to relieve the translation-inhibitory activity of dsRNA in reticulocyte lysates, by blocking the activation of the dsRNA-dependent enzymes. In addition, our results show that protein A, an S1133 core polypeptide, binds to dsRNA in an irreversible manner and that clearing this protein from extracts of infected cells abolishes their protranslational capacity. Taken together, our results raise the interesting possibility that protein A antagonizes the IFN-induced cellular response against avian reovirus by blocking the intracellular activation of enzyme pathways dependent on dsRNA, as has been suggested for several other viral dsRNA-binding proteins.The alpha/beta interferons (IFNs) are a family of multifunctional cytokines encoded by intronless genes, which are expressed and secreted by leukocytes and fibroblasts in response to viral infection and which have the same cell receptors (for recent reviews, see references 15, 22, 42, and 53). Extracellular IFNs bind to specific high-affinity cell surface receptors to trigger the activation of signal transduction pathways that, through a phosphorylation cascade, induce increased expression of the designated IFN-responsive genes (for reviews, see references 19, 43, 57, and 63). Three of the many alpha/beta IFN-inducible gene products have been shown to play an important role in fighting virus infection, namely, Mx proteins, the 2Ј,5Ј-oligoadenylate synthetase system (2-5A synthetase), and the double-stranded RNA (dsRNA)-activated protein kinase (PKR) (for reviews, see references 19, 28, 32, 39, 41, 45, 56, and 57). Mx proteins are a family of related GTPases that are thought to inhibit the viral polymerase activity of susceptible viruses (reviewed in reference 40). Both 2-5A synthetase and PKR antiviral pathways play a key role in the intracellular regulation of protein synthesis. Increased expression of these enzymes is induced by IFN, but they are latent until after activation by dsRNA (28, 45). The activated 2-5A synthetase catalyzes the synthesis of short oligonucleotides of the general structure ppp(A2Јp5Ј)nA. These oligonucleotides bind and stimulate a latent endoribonuclease, designated RNase L, to degrade both cellular and viral RNAs, thus preventing protein synthesis (for reviews, see references 44 and 54). Interaction of PKR with dsRNA results in autophosphorylation and dimerization of the...

show abstract

“…Thus, the results of Bialy and Colby (58) suggested that chIFN inhibits the synthesis of VV transcripts in CEF cells, whereas the results of Esteban and Metz (59) indicated that the cytokine induces viral protein synthesis inhibition while stimulating the synthesis of early VV transcripts. On the other hand, the study by Grün et al (60) suggested that priming CEF cells with IFN caused inhibition of VV protein synthesis by promoting the degradation of early viral transcripts, while the data of Degen et al (61) revealed that the degradation of VV mRNAs cannot be solely responsible for the inhibition of protein synthesis observed in IFN-treated VV-infected CEF cells. The results presented in the current study indicate that priming of avian cells with a recombinant chIFN-␣ induces viral protein synthesis inhibition and that PKR plays a key role in that inhibition.…”

Section: Discussionmentioning

confidence: 99%

Response of Three Different Viruses to Interferon Priming and Dithiothreitol Treatment of Avian Cells

Lostalé‐Seijo

Martı́nez-Costas

Benavente

2016

J Virol

View full text Add to dashboard Cite

We have previously shown that the replication of avian reovirus (ARV) in chicken cells is much more resistant to interferon (IFN) than the replication of vesicular stomatitis virus (VSV) or vaccinia virus (VV). In this study, we have investigated the role that the double-stranded RNA (dsRNA)-activated protein kinase (PKR) plays in the sensitivity of these three viruses toward the antiviral action of chicken interferon. Our data suggest that while interferon priming of avian cells blocks vaccinia virus replication by promoting PKR activation, the replication of vesicular stomatitis virus appears to be blocked at a pretranslational step. Our data further suggest that the replication of avian reovirus in chicken cells is quite resistant to interferon priming because this virus uses strategies to downregulate PKR activation and also because translation of avian reovirus mRNAs is more resistant to phosphorylation of the alpha subunit of initiation factor eIF2 than translation of their cellular counterparts. Our results further reveal that the avian reovirus protein sigmaA is able to prevent PKR activation and that this function is dependent on its double-stranded RNA-binding activity. Finally, this study demonstrates that vaccinia virus and avian reovirus, but not vesicular stomatitis virus, express/induce factors that counteract the ability of dithiothreitol to promote eIF2 phosphorylation. Our data demonstrate that each of the three different viruses used in this study elicits distinct responses to interferon and to dithiothreitol-induced eIF2 phosphorylation when infecting avian cells. IMPORTANCE Type I interferons constitute the first barrier of defense against viral infections, and one of the best characterized antiviral strategies is mediated by the double-stranded RNA-activated protein kinase R (PKR). The results of this study revealed that IFN priming of avian cells has little effect on avian reovirus (ARV) replication but drastically diminishes the replication of vaccinia virus (VV) and vesicular stomatitis virus (VSV)by PKR-dependent and -independent mechanisms, respectively. Our data also demonstrate that the dsRNA-binding ability of ARV protein sigmaA plays a key role in the resistance of ARV toward IFN by preventing PKR activation. Our findings will contribute to improve the current understanding of the interaction of viruses with the host's innate immune system. Finally, it would be of interest to uncover the mechanisms that allow avian reovirus transcripts to be efficiently translated under conditions (moderate eIF2 phosphorylation) that block the synthesis of cellular proteins. I nterferons (IFNs) comprise a family of multifunctional cytokines that were originally discovered by their strong antiviral activity and which are now recognized as the first barrier that viruses must overcome to establish a productive infection. Of the three IFN types, type I interferon (IFN-␣/␤) displays the highest antiviral activity, and its expression is induced in many cell types by viral infection or following c...

show abstract

Reduced steady-state levels of vaccinia virus-specific early mRNAs in interferon-treated chick embryo fibroblasts

Cited by 12 publications

References 18 publications

The 2–5 A system: Modulation of viral and cellular processes through acceleration of RNA degradation

The 2–5 A system: Modulation of viral and cellular processes through acceleration of RNA degradation

Possible Involvement of the Double-Stranded RNA-Binding Core Protein ςA in the Resistance of Avian Reovirus to Interferon

Response of Three Different Viruses to Interferon Priming and Dithiothreitol Treatment of Avian Cells

Contact Info

Product

Resources

About