Induction of Suppressor of Cytokine Signaling-3 by Herpes Simplex Virus Type 1 Contributes to Inhibition of the Interferon Signaling Pathway

Abstract

We showed previously that herpes simplex virus type 1 (HSV-1) suppresses the interferon (IFN) signaling pathway during the early infection stage in the human amnion cell line FL. HSV-1 inhibits the IFN-induced phosphorylation of Janus kinases (JAK) in infected FL cells. In the present study, we showed that the suppressor of cytokine signaling-3 (SOCS3), a host negative regulator of the JAK/STAT pathway, is rapidly induced in FL cells after HSV-1 infection. Maximal levels of SOCS3 protein were detected at around 1 to 2 h after infection. This is consistent with the occurrence of HSV-1-mediated inhibition of IFN-induced JAK phosphorylation. The HSV-1 wild-type strain VR3 induced SOCS3 more efficiently than did mutants that are defective in UL41 or UL13 and that are hyperresponsive to IFN. Induction of the IRF-7 protein and transcriptional activation of IFN-␣4, which occur in a JAK/STAT pathway-dependent manner, were poorly induced by VR3 but efficiently induced by the mutant viruses. In contrast, phosphorylation of IRF-3 and transcriptional activation of IFN-␤, which are JAK/STAT pathway-independent process, were equally well induced by the wild-type strain and the mutants. In conclusion, the SOCS3 protein appears to be mainly responsible for the suppression of IFN signaling and IFN production that occurs during HSV-1 infection.Cells have various defense mechanisms that protect them from viral infection. In turn, viruses suppress or escape host responses by a variety of strategies. Interferon (IFN) is induced by viral infection and plays an important role in the defense of the host cell from viral attack. When IFN binds to specific cell surface receptors on the host cells, it promotes the antiviral state through induction or activation of the 2Ј,5Ј-oligoadenylate synthetase (2-5AS)/RNase L system, the double-stranded RNA-activated protein kinase, and the MxA protein (10,30,35). The signal transduction pathway of IFN consists of Janus kinases (JAK), tyrosine protein kinases that interact with the intracellular domains of the receptors, and the STAT family proteins, transcription factors that are activated by their phosphorylation by JAK. This pathway, which is designated the JAK/STAT pathway, also transduces various cytokine signals. There are four JAK proteins (Jak1, Jak2, Jak3, and Tyk2) and seven STAT proteins (STAT1 to 4, STAT5a, STAT5b, and STAT6) (1, 9, 17, 25). Each cytokine employs a particular combination of the JAK and STAT proteins, which determines the specificity of the cytokine responses. For instance, Jak1 and Tyk2 are associated with the IFN-␣/␤ receptor complex. These JAK proteins are activated by phosphorylation after IFN-␣/␤ binds to the receptor, and they then phosphorylate STAT1 and STAT2. The transcription factor ISGF3, which consists of phosphorylated STAT1, phosphorylated STAT2, and IRF-9/ p48/ISGF3␥, forms and then translocates into the nucleus and binds to IFN-stimulated response elements in the promoters of IFN-inducible genes (9, 12).DNA and RNA viruses use various strategies to countera...

Interferons and viruses: an interplay between induction, signalling, antiviral responses and virus countermeasures

“…In contrast to interfering directly with STAT1 or STAT2, VP24 of EBOV (Reid et al, 2006) and the ORF6 protein of SARS-CoA (Frieman et al, 2007) interact with karyopherin to inhibit the nuclear import of STATs. As part of its mechanism to circumvent the IFN response, HSV rapidly induces the expression of SOCS3, a cellular inhibitor of JAK/STAT pathways (Yokota et al, 2004), as reportedly does the HCV core protein (Bode et al, 2003). HCV and HBV have also been reported to upregulate the expression of protein phosphatase 2A (PP2A), which can interfere with STAT signalling (Duong et al, 2004;Christen et al, 2007).…”

Molecular mechanisms of HLA class I antigen abnormalities following viral infection and transformation

“…134 HSV-1 also negatively interferes with the JAK/STAT1 pathway by inducing the suppressor of cytokine signaling (SOCS)-3 molecule. 135 …”

The PPE18 Protein of Mycobacterium tuberculosis Inhibits NF-κB/rel–Mediated Proinflammatory Cytokine Production by Upregulating and Phosphorylating Suppressor of Cytokine Signaling 3 Protein

“…It appears that PPE18 probably targets the proinflammatory signaling downstream of TLR2 by activating certain negative regulators of this pathway. Interestingly, suppressor of cytokine signaling 3 (SOCS3) downstream of TLR2 (25) acts as negative regulator of proinflammatory signaling (26)(27)(28)(29). Because several pathogenic mycobacterial species induce expression of the SOCS3 protein (30)(31)(32), we speculated that probably SOCS3 protein is involved in the suppression of induction of IL-12 p40 in macrophages treated with PPE18.…”