Characterization of a vaccinia virus-encoded double-stranded RNA-binding protein that may be involved in inhibition of the double-stranded rna-dependent protein kinase

Watson, Julia C.; Chang, Hwai-Wen; Jacobs, Bertram L.

doi:10.1016/0042-6822(91)90768-7

Cited by 118 publications

(97 citation statements)

References 20 publications

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“…The VV E3L gene encodes two proteins, p25 and p20 (373), expressed early in infection (395). E3L is a host range gene, necessary for efficient VV replication in several cell lines (15), and is required for VV pathogenesis (30).…”

Section: Vol 70 2006 Impact Of Protein Kinase Pkr In Cell Biology 1045mentioning

confidence: 99%

“…The resistance conferred by the capsid 3 protein is certainly incomplete, however, since mammalian reoviruses are not protected against high levels of PKR activity, as found in most untransformed cells and in IFN-treated cells. Avian reoviruses express the A protein, which has much stronger dsRNA-binding affinity than 3 and interferes efficiently with PKR function (130,242), corresponding with lower IFN sensitivity of avian in comparison with mammalian reoviruses (242,334,373).…”

Section: Orthomyxovirus: Influenza Virusmentioning

confidence: 99%

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Impact of Protein Kinase PKR in Cell Biology: from Antiviral to Antiproliferative Action

García

Gil

Ventoso

et al. 2006

Microbiol Mol Biol Rev

694

731

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SUMMARY The double-stranded RNA-dependent protein kinase PKR is a critical mediator of the antiproliferative and antiviral effects exerted by interferons. Not only is PKR an effector molecule on the cellular response to double-stranded RNA, but it also integrates signals in response to Toll-like receptor activation, growth factors, and diverse cellular stresses. In this review, we provide a detailed picture on how signaling downstream of PKR unfolds and what are the ultimate consequences for the cell fate. PKR activation affects both transcription and translation. PKR phosphorylation of the alpha subunit of eukaryotic initiation factor 2 results in a blockade on translation initiation. However, PKR cannot avoid the translation of some cellular and viral mRNAs bearing special features in their 5′ untranslated regions. In addition, PKR affects diverse transcriptional factors such as interferon regulatory factor 1, STATs, p53, activating transcription factor 3, and NF-κB. In particular, how PKR triggers a cascade of events involving IKK phosphorylation of IκB and NF-κB nuclear translocation has been intensively studied. At the cellular and organism levels PKR exerts antiproliferative effects, and it is a key antiviral agent. A point of convergence in both effects is that PKR activation results in apoptosis induction. The extent and strength of the antiviral action of PKR are clearly understood by the findings that unrelated viral proteins of animal viruses have evolved to inhibit PKR action by using diverse strategies. The case for the pathological consequences of the antiproliferative action of PKR is less understood, but therapeutic strategies aimed at targeting PKR are beginning to offer promising results.

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Section: Vol 70 2006 Impact Of Protein Kinase Pkr In Cell Biology 1045mentioning

confidence: 99%

Section: Orthomyxovirus: Influenza Virusmentioning

confidence: 99%

Impact of Protein Kinase PKR in Cell Biology: from Antiviral to Antiproliferative Action

García

Gil

Ventoso

et al. 2006

Microbiol Mol Biol Rev

694

731

View full text Add to dashboard Cite

show abstract

“…K3L is a PKR pseudosubstrate and E3L is a high affinity dsRNA-binding protein (Davies et al, 1993). The E3L gene of VV encodes two proteins, p25 and p20 (Watson et al, 1991) that are expressed early in infection (Yuwen et al, 1993) and are incorporated in the virions of VV (Murcia-Nicolas et al, 1999). E3L is a host range gene, necessary for efficient VV replication in several cell lines (Beattie et al, 1995) and is required for VV pathogenesis (Brandt and Jacobs, 2001).…”

Section: Introductionmentioning

confidence: 99%

Anti-apoptotic and oncogenic properties of the dsRNA-binding protein of vaccinia virus, E3L

et al. 2002

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The vaccinia virus (VV) E3L gene encodes a dsRNA binding protein that inhibits activation of the IFNinduced, dsRNA-dependent protein kinase, (PKR), the 2 -5A synthetases/RNase L system and other dsRNA dependent pathways, thus leading to efficient VV replication. To analyse E3L effects over cellular metabolism in a virus-free system, we have generated stable mouse 3T3 cell lines expressing E3L. Expression of E3L in NIH3T3 cells results in inhibition of eIF-2a phosphorylation and IkBa degradation in response to dsRNA. Antiviral responses induced by IFN-a/b were partially impaired in 3T3-E3L cells, as determined by a viability assay upon VSV infection. E3L expression also confers resistance to dsRNA-triggered apoptosis. Interestingly, cells expressing E3L grew faster than control cells, and showed increased expression of cyclin A and decreased levels of p27 Kip1 . E3L cooperated with H-ras in a focus formation assay, and NIH3T3 E3L cells formed solid tumors when injected in nude mice. Overall, our findings reveal that interference of E3L protein with several cellular pathways, results in promotion of cellular growth, impairment of antiviral activity and resistance to apoptosis.

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“…VA RNA I , encoded by adenovirus, binds to the DRBMs but fails to activate the enzyme. The vaccinia virus E3L product is a dsRNA-binding protein capable of inhibiting PKR by sequestering dsRNA activators (3,7,26,49).…”

mentioning

confidence: 99%

Inhibition of Double-Stranded RNA-Dependent Protein Kinase PKR by Vaccinia Virus E3: Role of Complex Formation and the E3 N-Terminal Domain

Romano

Zhang

Tan

et al. 1998

Molecular and Cellular Biology

174

181

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The human double-stranded RNA (dsRNA)-dependent protein kinase PKR inhibits protein synthesis by phosphorylating translation initiation factor 2α (eIF2α). Vaccinia virus E3Lencodes a dsRNA binding protein that inhibits PKR in virus-infected cells, presumably by sequestering dsRNA activators. Expression of PKR in Saccharomyces cerevisiae inhibits protein synthesis by phosphorylation of eIF2α, dependent on its two dsRNA binding motifs (DRBMs). We found that expression of E3 in yeast overcomes the lethal effect of PKR in a manner requiring key residues (Lys-167 and Arg-168) needed for dsRNA binding by E3 in vitro. Unexpectedly, the N-terminal half of E3, and residue Trp-66 in particular, also is required for anti-PKR function. Because the E3 N-terminal region does not contribute to dsRNA binding in vitro, it appears that sequestering dsRNA is not the sole function of E3 needed for inhibition of PKR. This conclusion was supported by the fact that E3 activity was antagonized, not augmented, by overexpressing the catalytically defective PKR-K296R protein containing functional DRBMs. Coimmunoprecipitation experiments showed that a majority of PKR in yeast extracts was in a complex with E3, whose formation was completely dependent on the dsRNA binding activity of E3 and enhanced by the N-terminal half of E3. In yeast two-hybrid assays and in vitro protein binding experiments, segments of E3 and PKR containing their respective DRBMs interacted in a manner requiring E3 residues Lys-167 and Arg-168. We also detected interactions between PKR and the N-terminal half of E3 in the yeast two-hybrid and λ repressor dimerization assays. In the latter case, the N-terminal half of E3 interacted with the kinase domain of PKR, dependent on E3 residue Trp-66. We propose that effective inhibition of PKR in yeast requires formation of an E3-PKR-dsRNA complex, in which the N-terminal half of E3 physically interacts with the protein kinase domain of PKR.

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Characterization of a vaccinia virus-encoded double-stranded RNA-binding protein that may be involved in inhibition of the double-stranded rna-dependent protein kinase

Cited by 118 publications

References 20 publications

Impact of Protein Kinase PKR in Cell Biology: from Antiviral to Antiproliferative Action

Impact of Protein Kinase PKR in Cell Biology: from Antiviral to Antiproliferative Action

Anti-apoptotic and oncogenic properties of the dsRNA-binding protein of vaccinia virus, E3L

Inhibition of Double-Stranded RNA-Dependent Protein Kinase PKR by Vaccinia Virus E3: Role of Complex Formation and the E3 N-Terminal Domain

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