Herpes Simplex Virus 1 Gene Products Occlude the Interferon Signaling Pathway at Multiple Sites

Chee, Ana; Roizman, Bernard

doi:10.1128/jvi.78.8.4185-4196.2004

Cited by 106 publications

(111 citation statements)

References 65 publications

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“…The E6 protein of human papillomavirus 18 binds to Tyk2 and prevents its normal association with the IFNAR1 subunit, thereby inhibiting JAK-STAT signaling (29). Inhibition of JAK phosphorylation has also been associated with suppression of JAK-STAT signaling following infection with human herpes simplex virus type 1 (inhibited phosphor-ylation of Jak1, Jak2, and Tyk2) (7,56), Sendai virus (Tyk2) (23), and measles virus (Jak1) (55). The precise mechanism(s) by which flaviviruses circumvent JAK-STAT signaling remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Interferon-Stimulated JAK-STAT Signaling by a Tick-Borne Flavivirus and Identification of NS5 as an Interferon Antagonist

Best

Morris

Shannon³

et al. 2005

J Virol

285

276

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Section: Discussionmentioning

confidence: 99%

Inhibition of Interferon-Stimulated JAK-STAT Signaling by a Tick-Borne Flavivirus and Identification of NS5 as an Interferon Antagonist

Best

Morris

Shannon³

et al. 2005

J Virol

285

276

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“…Among the herpesvirus family, STAT2 degradation has been reported for herpes simplex virus-1 (Chee & Roizman, 2004), MCMV (Zimmermann et al, 2005) and murine gammaherpesvirus-68 (Liang et al, 2004). At the molecular level, the paradigm for virus-induced STAT degradation is given by the simian virus 5 V protein that targets STATs to the proteasome by forming a DDB1-Cul4A degradation complex (Precious et al, 2005); the crystal structure of this has recently been resolved (Guma et al, 2006).…”

Section: Stat2 As a Target Of Hcmv Interference With Ifn Signallingmentioning

confidence: 99%

Human cytomegalovirus interferes with signal transducer and activator of transcription (STAT) 2 protein stability and tyrosine phosphorylation

Trilling

Wilborn

et al. 2008

Journal of General Virology

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We have investigated the role of signal transducer and activator of transcription (STAT) 2 during human cytomegalovirus (HCMV) replication and found that protein levels of STAT2 are downregulated. STAT2 downregulation was observed in HCMV clinical isolates and laboratory strains with the exception of strain Towne. The HCMV-induced loss of STAT2 protein occurred despite an increased accumulation of STAT2 mRNA; it required HCMV early gene expression. The decrease in STAT2 was sensitive to proteasome inhibition, suggesting degradation of STAT2 via the ubiquitin proteasome pathway. Notably, pUL27, the HCMV homologue of the mouse CMV pM27 protein, which mediates the selective proteolysis of STAT2, did not induce STAT2 downregulation. Moreover, preceding STAT2 degradation, alpha/beta interferon (IFN)-receptormediated tyrosine phosphorylation of STAT2 was inhibited in HCMV-infected cells. This effect was paralleled by impaired tyrosine activation of STAT1 and STAT3. Accordingly, IFNs affected the replication efficiency of STAT2 degrading and non-degrading HCMV strains to a similar degree. In summary, HCMV abrogates IFN receptor signalling at multiple checkpoints by independent mechanisms including UL27-independent degradation of STAT2 and a preceding blockade of STAT2 phosphorylation. INTRODUCTIONCytomegaloviruses (CMVs) are members of the betaherpesvirus sub-family which persist for life in infected hosts through consecutive phases of productive and latent infection. While infection of immunocompetent individuals is usually subclinical, human cytomegalovirus (HCMV) can cause severe disease in transplant patients, people with primary or acquired immundeficiency or newborns after congenital infection (Mocarski et al., 2007). Immune control of mouse CMV (MCMV) infection is organized in a hierarchical and redundant manner by distinct components of innate and adaptive immunity (Polic et al., 1998). Interferons (IFNs) provide a direct defence against CMVs and connect innate and adaptive immunity (Lucin et al., 1992;Heise et al., 1998;Polic et al., 1998). Binding of IFN-a/b and IFN-c to their cognate transmembrane receptors initiates distinct Jak-signal transducer and activator of transcription (Jak-STAT)-dependent signalling pathways (Darnell, 1997;Stark et al., 1998). IFN receptors are composed of two subunits. Upon ligand binding, receptor-associated Jak kinases are activated and phosphorylate STAT proteins which subsequently dimerize, translocate to the nucleus and induce IFNdependent gene expression. Experimental studies using MCMV indicate that IFN receptor-induced Jak-STAT signalling has an indispensable role in the control of CMV replication by the host immune system (Lucin et al., 1992(Lucin et al., , 1994Heise et al., 1998;Presti et al., 1998). By replicating under the selective pressure of IFNs, CMVs have evolved effective mechanisms that counteract IFN induction (Le et al., 2008) and IFN-mediated antiviral defence mechanisms Zimmermann & Hengel, 2006).CMVs are able to interfere with IFN-dependent signal transdu...

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“…According to Chee et al (36), one of the mechanisms for herpes simplex virus to block STAT activation is mediated through downregulation of IFNAR expression. To investigate whether this mechanism was also operating in DV infection, the expression of IFNAR1 and IFNAR2 after mock or DV infection was determined by a flow cytometer.…”

Section: Blocked Antiviral Effect Of Ifn-␣ Through Targeting Tyk2 mentioning

confidence: 99%

Dengue Virus Type 2 Antagonizes IFN-α but Not IFN-γ Antiviral Effect via Down-Regulating Tyk2-STAT Signaling in the Human Dendritic Cell

Ho¹,

Hung²,

Weng

et al. 2005

The Journal of Immunology

137

129

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The immunopathogenesis mechanism of dengue virus (DV) infection remains elusive. We previously showed that the target of DV in humans is dendritic cells (DCs), the primary sentinels of immune system. We also observed that despite the significant amount of IFN-α induced; DV particles remain massively produced from infected DCs. It suggests that DV may antagonize the antiviral effect of IFN-α. Recent work in animal studies demonstrated the differential critical roles of antiviral cytokines, namely IFN-α/IFN-β and IFN-γ, in blocking early viral production and in preventing viral-mediated disease, respectively. In this study, we examined the effects of IFN-α and IFN-γ in DV infection of monocyte-derived DCs. We showed that the preinfection treatment with either IFN-α or IFN-γ effectively armed DCs and limited viral production in infected cells. However, after infection, DV developed mechanisms to counteract the protection from lately added IFN-α, but not IFN-γ. Such a selective antagonism on antiviral effect of IFN-α, but not IFN-γ, correlated with down-regulated tyrosine-phosphorylation and DNA-binding activities of STAT1 and STAT3 transcription factors by DV. Furthermore, subsequent studies into the underlying mechanisms revealed that DV attenuated IFN-α-induced tyrosine-phosphorylation of Tyk2, an upstream molecule of STAT activation, but had no effect on expression of both IFN-α receptor 1 and IFN-α receptor 2. Moreover, DV infection by itself could activate STAT1 and STAT3 through IFN-α-dependent and both IFN-α-dependent and IFN-α-independent mechanisms, respectively. These observations provide very useful messages with physiological significance in investigation of the pathogenesis, the defense mechanisms of human hosts and the therapeutic considerations in DV infection.

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Herpes Simplex Virus 1 Gene Products Occlude the Interferon Signaling Pathway at Multiple Sites

Cited by 106 publications

References 65 publications

Inhibition of Interferon-Stimulated JAK-STAT Signaling by a Tick-Borne Flavivirus and Identification of NS5 as an Interferon Antagonist

Inhibition of Interferon-Stimulated JAK-STAT Signaling by a Tick-Borne Flavivirus and Identification of NS5 as an Interferon Antagonist

Human cytomegalovirus interferes with signal transducer and activator of transcription (STAT) 2 protein stability and tyrosine phosphorylation

Dengue Virus Type 2 Antagonizes IFN-α but Not IFN-γ Antiviral Effect via Down-Regulating Tyk2-STAT Signaling in the Human Dendritic Cell

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