The Amino Terminus of the Vaccinia Virus E3 Protein Is Necessary To Inhibit the Interferon Response

White, Stacy D.; Jacobs, Bertram L.

doi:10.1128/jvi.06889-11

Cited by 40 publications

(57 citation statements)

References 43 publications

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“…Thus, while the E3L ZBD has a nucleic acid-binding independent function to inhibit PKR, the nucleic binding property of this domain is important for viral pathogenicity. Taken together, these results lead us to suggest that the Z-DNA binding properties of E3L are necessary for the inhibition of other components of the interferon-induced anti-viral defense, consistent with the recent report that the pathogenicity of ΔE3L vaccinia virus is fully rescued by knockout of the type I interferon receptor in mice (White and Jacobs 2012).…”

Section: Discussionsupporting

confidence: 71%

Variola virus E3L Zα domain, but not its Z-DNA binding activity, is required for PKR inhibition

Thakur

Seo

Dever

2013

RNA

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Responding to viral infection, the interferon-induced, double-stranded RNA (dsRNA)-activated protein kinase PKR phosphorylates translation initiation factor eIF2α to inhibit cellular and viral protein synthesis. To overcome this host defense mechanism, many poxviruses express the protein E3L, containing an N-terminal Z-DNA binding (Zα) domain and a C-terminal dsRNA-binding domain (dsRBD). While E3L is thought to inhibit PKR activation by sequestering dsRNA activators and by directly binding the kinase, the role of the Zα domain in PKR inhibition remains unclear. Here, we show that the E3L Zα domain is required to suppress the growth-inhibitory properties associated with expression of human PKR in yeast, to inhibit PKR kinase activity in vitro, and to reverse the inhibitory effects of PKR on reporter gene expression in mammalian cells treated with dsRNA. Whereas previous studies revealed that the Z-DNA binding activity of E3L is critical for viral pathogenesis, we identified point mutations in E3L that functionally uncouple Z-DNA binding and PKR inhibition. Thus, our studies reveal a molecular distinction between the nucleic acid binding and PKR inhibitory functions of the E3L Zα domain, and they support the notion that E3L contributes to viral pathogenesis by targeting PKR and other components of the cellular anti-viral defense pathway.

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Section: Discussionsupporting

confidence: 71%

Variola virus E3L Zα domain, but not its Z-DNA binding activity, is required for PKR inhibition

Thakur

Seo

Dever

2013

RNA

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“…On the other hand, Zalpha domains are a feature of the poxviral protein E3L, which is present in all known poxviruses and which is crucial for the subversion of the host interferon response. The E3L protein acts through the inhibition of PKR (11) and has also been suggested to inhibit the action of DAI, a cytoplasmic sensor of nucleic acids with two Zalpha domains. Finding a similar virus evasion protein in Alloherpesviridae is consistent with previous work which identified similarities between genes encoding thymi-dylate monophosphate kinase (TmpK), ribonucleotide reductase and thymidine kinase in poxviruses and the family Alloherpesviridae, suggesting that Alloherpesviridae may be evolutionarily related to poxviruses (14).…”

Section: Discussionmentioning

confidence: 99%

“…Thus, strains with nonfunctional E3L dramatically lose their proliferation potential. The E3L protein consists of two domains, a C-terminal dsRNAbinding domain (dsRBD) and an N-terminal Zalpha domain, and both domains have been shown to be required to fully block host responses (11). Surprisingly, however, no other virus family has been found to encode a Zalpha-containing protein.…”

mentioning

confidence: 99%

Crystal Structure of a Poxvirus-Like Zalpha Domain from Cyprinid Herpesvirus 3

Tomé

Kuś

Correia

et al. 2013

J Virol

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Zalpha domains are a subfamily of the winged helix-turn-helix domains sharing the unique ability to recognize CpG repeats in the left-handed Z-DNA conformation. In vertebrates, domains of this family are found exclusively in proteins that detect foreign nucleic acids and activate components of the antiviral interferon response. Moreover, poxviruses encode the Zalpha domaincontaining protein E3L, a well-studied and potent inhibitor of interferon response. Here we describe a herpesvirus Zalpha-domain-containing protein (ORF112) from cyprinid herpesvirus 3. We demonstrate that ORF112 also binds CpG repeats in the left-handed conformation, and moreover, its structure at 1.75 Å reveals the Zalpha fold found in ADAR1, DAI, PKZ, and E3L. Unlike other Zalpha domains, however, ORF112 forms a dimer through a unique domain-swapping mechanism. Thus, ORF112 may be considered a new member of the Z-domain family having DNA binding properties similar to those of the poxvirus E3L inhibitor of interferon response.

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“…Moreover, we have previously demonstrated that a poxvirus E3L ortholog, such as sheeppox virus 034, does not supplement the biological functions of the E3 protein, although it binds dsRNA (18). It also has been reported that the ZBD plays a role in inhibition of interferon induction (19) and full pathogenesis in vivo in mice (14,20,21). Thus, it is inconclusive what role the biochemical capacity of dsRNA binding plays in the biological functions of the E3 protein.…”

mentioning

confidence: 95%

“…Since it has been reported that the N-terminal Z-DNA binding domain also is important for the complete biological functions of the E3 protein (14,(19)(20)(21), it would be interesting to examine the mutants (described in this report) in the system for identification of the biological functions of the Z-DNA binding domain. In addition, it will be interesting to investigate what correlation the described mutants will demonstrate with other reported functions attributed to vaccinia E3 protein, such as inhibition of cytokine in primary cells and dendritic cells (37,38) and inhibition of ISG15 (39).…”

Section: Figmentioning

confidence: 99%

Mutational Analysis of Vaccinia Virus E3 Protein: the Biological Functions Do Not Correlate with Its Biochemical Capacity To Bind Double-Stranded RNA

Dueck

Chen

et al. 2015

J Virol

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Poxviridae is a diverse family of large dsDNA viruses (130 to 300 kb) which replicate exclusively in the cytoplasm of infected cells and exhibit a varied host range (1). Some members are specific to a single host, such as variola virus, the causative agent of smallpox, while others, such as vaccinia virus, display a broad host range. Poxviruses encode a number of immunomodulatory proteins, e.g., host range proteins (2). Orthopoxviruses encode a number of host range genes, such as SPI-1, K1L, C7L, p28/N1R, B5R, K3L, and E3L, the alteration or deletion of which restricts the virus replication in specific cell lines (3). These host range genes display varied restrictions and biological functions. For example, SPI-1 is required for vaccinia virus replication in PK15 and A549 cells and in mice (4, 5). K1L, an ankyrin repeat-containing protein which inhibits IkB-␣ degradation and interferon (IFN)-stimulated effectors, is required for replication in RK13 cells (6). A double deletion of C7L and K1L leads to restriction of the virus replication in PK1, RK13, and multiple human cell lines, while C7L deletion alone suppresses apoptosis and limits replication in hamster Dede cells (7). P28/N1R, an E3-RING finger ubiquitin ligase involved in protein degradation and apoptosis suppression, is required for replication in mouse macrophage (8, 9), while B5R, a membrane glycoprotein, activates Src, allowing growth in VERO, CEF, PK15, and quail (QT-6) cells (10).The most studied vaccinia host range gene is E3L. E3 protein is expressed early in the virus replication cycle and is known to suppress multiple innate immune pathways (3,11,12). E3 protein possesses biochemical capacities to bind Z-form DNA via the Z-DNA binding domain (ZBD) toward the N terminus and to bind to dsRNA through the C-terminal dsRNA binding domain (DRBD) (13,14). Since the best characterized biological functions of vaccinia virus E3 protein, such as host range function and inhibition of innate immune responses (e.g., cytokine expression, apoptosis and interferon-induced antiviral activity), all are mediated primarily via the DRBD region of E3 protein (15-17), generally it has been believed that E3 protein functions through seques-

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The Amino Terminus of the Vaccinia Virus E3 Protein Is Necessary To Inhibit the Interferon Response

Cited by 40 publications

References 43 publications

Variola virus E3L Zα domain, but not its Z-DNA binding activity, is required for PKR inhibition

Variola virus E3L Zα domain, but not its Z-DNA binding activity, is required for PKR inhibition

Crystal Structure of a Poxvirus-Like Zalpha Domain from Cyprinid Herpesvirus 3

Mutational Analysis of Vaccinia Virus E3 Protein: the Biological Functions Do Not Correlate with Its Biochemical Capacity To Bind Double-Stranded RNA

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