STAT2 Is a Pervasive Cytokine Regulator due to Its Inhibition of STAT1 in Multiple Signaling Pathways

Severe complications of Zika virus (ZIKV) infection might be caused by inflammation, but how ZIKV induces proinflammatory cytokines is not understood. In this study, we show opposite regulatory effects of the ZIKV NS5 protein on interferon (IFN) signaling. Whereas ZIKV and its NS5 protein were potent suppressors of type I and type III IFN signaling, they were found to activate type II IFN signaling. Inversely, IFN-␥ augmented ZIKV replication. NS5 interacted with STAT2 and targeted it for ubiquitination and degradation, but it had no influence on STAT1 stability or nuclear translocation. The recruitment of STAT1-STAT2-IRF9 to IFN-␤-stimulated genes was compromised when NS5 was expressed. Concurrently, the formation of STAT1-STAT1 homodimers and their recruitment to IFN-␥-stimulated genes, such as the gene encoding the proinflammatory cytokine CXCL10, were augmented. Silencing the expression of an IFN-␥ receptor subunit or treatment of ZIKV-infected cells with a JAK2 inhibitor suppressed viral replication and viral induction of IFN-␥-stimulated genes. Taken together, our findings provide a new mechanism by which the ZIKV NS5 protein differentially regulates IFN signaling to facilitate viral replication and cause diseases. This activity might be shared by a group of viral IFN modulators.IMPORTANCE Mammalian cells produce three types of interferons to combat viral infection and to control host immune responses. To replicate and cause diseases, pathogenic viruses have developed different strategies to defeat the action of host interferons. Many viral proteins, including the Zika virus (ZIKV) NS5 protein, are known to be able to suppress the antiviral property of type I and type III interferons. Here we further show that the ZIKV NS5 protein can also boost the activity of type II interferon to induce cellular proteins that promote inflammation. This is mediated by the differential effect of the ZIKV NS5 protein on a pair of cellular transcription factors, STAT1 and STAT2. NS5 induces the degradation of STAT2 but promotes the formation of STAT1-STAT1 protein complexes, which activate genes controlled by type II interferon. A drug that specifically inhibits the IFN-␥ receptor or STAT1 shows an anti-ZIKV effect and might also have anti-inflammatory activity.KEYWORDS Zika virus, NS5 protein, type II interferon, STAT1, STAT2 Z ika virus (ZIKV) is a member of the Flaviviridae family with a positive-sense RNA genome of about 10 kb (1). Similar to other flaviviruses, such as yellow fever virus, dengue virus, and Japanese encephalitis virus, ZIKV expresses a single polypeptide which is proteolytically processed into 3 structural (C, prM, and E) and 7 nonstructural (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5) proteins. ZIKV is an arbovirus transmitted to humans through the bites of mosquitoes of the species Aedes aegypti and, to a lesser extent, Aedes albopictus (2). Since its discovery in 1947 (3), ZIKV had been known to cause only mild and self-limiting febrile diseases, with a majority of patients being

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“…6). These findings, together with other recent findings reported in a related paper (52), are depicted in Fig. 8.…”

Section: Discussionsupporting

confidence: 89%

“…7C, bar 3 versus bar 2). The inhibitory effect of STAT2 on IFN-␥ signaling observed here is consistent with recent findings reported in the literature (52). Interestingly, the expression of NS5 in U6A cells did not enhance IFN-␥-induced activation of GAS-Luc (Fig.…”

supporting

confidence: 93%

Selective Activation of Type II Interferon Signaling by Zika Virus NS5 Protein

Chaudhary

Yuen

Chan

et al. 2017

J Virol

112

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“…At the plasma membrane, suppressor of cytokine signaling proteins block receptor activation by binding to the activated JAK catalytic sites, thus turning off downstream signals. Moreover, at the cytoplasm, an increase in un-phosphorylated STAT2 binds pStat1 to diminish its nuclear translocation during continuous IFN␥ stimulation possibly eliciting adaptation to long-term IFN␥ stimulation (71). In the nuclei, protein inhibitors of activated STAT (PIAS) associate with activated STAT dimers via their zinc-binding ring finger domain in the center of the molecule, preventing them from binding to the DNA (72).…”

Section: Chronic Exposure To Ifn␥ Leads To Adsmentioning

confidence: 99%

Current prospects of type II interferon γ signaling and autoimmunity

Green

Young

Valencia

2017

Journal of Biological Chemistry

130

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Edited by Charles E. SamuelInterferon ␥ (IFN␥) is a pleiotropic protein secreted by immune cells. IFN␥ signals through the IFN␥ receptor, a protein complex that mediates downstream signaling events. Studies into IFN␥ signaling have provided insight into the general concepts of receptor signaling, receptor internalization, regulation of distinct signaling pathways, and transcriptional regulation. Although IFN␥ is the central mediator of the adaptive immune response to pathogens, it has been shown to be involved in several non-infectious physiological processes. This review will provide an introduction into IFN␥ signaling biology and the functional roles of IFN␥ in the autoimmune response.According to the National Institutes of Health, autoimmune diseases (ADs) 3 are one of the top 10 leading causes of death in female children and women in all age groups up to 64 years of age (1). Excess secretion of IFNs has been associated with development of human ADs (2). Interferons (IFNs) comprise a family of proteins classified as type I (IFN-␣, -␤, -⑀, -, and -), type II (IFN-␥, herein IFN␥), and type III (IFN-1-4) that have pleiotropic roles in immunity, cancer biology, and autoimmunity (2). Here, we aim to provide a basic understanding of the functions of the type II IFN␥ and the IFN␥-signaling pathway (hereafter referred to as IFN signaling) in a contextual and timing perspective related to the autoimmune environment and the development of ADs.

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“…However, for STAT1 only, this phenomenon can be prevented by modification of the protein by SUMO Droescher et al 2011). STAT2 forms a stable antiparallel heterodimer with either the unphosphorylated or tyrosine-phosphorylated forms of STAT1; these heterodimers are not transported to the nucleus and have no transcriptional activity, so STAT2 is a pervasive negative regulator of STAT1-dependent functions (Ho et al 2016). However, when IRF9 is present in sufficient quantity, antiparallel STAT1-STAT2 heterodimers will be converted to U-ISGF3 or to hemiphosphorylated ISGF3 (Morrow et al 2011), in which the relative orientation of the two STATs becomes parallel.…”

Section: Structures and Intracellular Locations Of Statsmentioning

confidence: 99%

“…They are then transported to the nucleus and bind to DNA to activate transcription. Thus, the availability of free STAT1 to signal in response, for example, to IFN-g or IL-27 (Ho et al 2016), will depend on the relative concentrations of both STAT2 and IRF9.…”

Section: Structures and Intracellular Locations Of Statsmentioning

confidence: 99%

Responses to Cytokines and Interferons that Depend upon JAKs and STATs

Stark

Cheon

Wang

2017

Cold Spring Harb Perspect Biol

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Many cytokines and all interferons activate members of a small family of kinases (the Janus kinases [JAKs]) and a slightly larger family of transcription factors (the signal transducers and activators of transcription [STATs]), which are essential components of pathways that induce the expression of specific sets of genes in susceptible cells. JAK-STAT pathways are required for many innate and acquired immune responses, and the activities of these pathways must be finely regulated to avoid major immune dysfunctions. Regulation is achieved through mechanisms that include the activation or induction of potent negative regulatory proteins, posttranslational modification of the STATs, and other modulatory effects that are cell-type specific. Mutations of JAKs and STATs can result in gains or losses of function and can predispose affected individuals to autoimmune disease, susceptibility to a variety of infections, or cancer. Here we review recent developments in the biochemistry, genetics, and biology of JAKs and STATs. Because the basic biochemistry of Janus kinase -signal transducers and activators of transcription (JAK-STAT) signaling pathways has been frequently and extensively reviewed (see, for example, Stark and Darnell 2012;Cai et al. 2015;O'Shea et al. 2015;Villarino et al. 2015), we present here only a brief summary. After a cytokine or interferon binds to its specific receptor, the receptor forms homodimers, heterodimers, or trimers, depending on the cytokine, thus activating the tightly bound JAKs to cross-phosphorylate each other. The activated JAKs then phosphorylate specific tyrosine residues in the cytoplasmic domains of the receptors, providing binding sites for the STATs through their highly conserved SH2 domains. The receptor-bound STATs are phosphorylated, each on a highly conserved tyrosine residue, after which they leave the receptor as homo-or heterodimers whose association is strengthened by SH2-phosphotyrosine interactions. The phosphorylated STAT dimers are then transported to the nucleus, where they bind to and activate specific promoters. The basic outline of JAK-STAT signaling (Fig. 1) shows that interferon (IFN)-g (type II IFN) and all of the cytokines primarily drive the formation of specific STAT homodimers, which then bind to DNA directly. However, in some cases, heterodimers involving STAT1 and STAT3 or STAT5A and STAT5B can also form. In contrast, IFN-b and the subtypes of IFN-a (collectively type I IFNs) and the subtypes of IFN-l (collectively type III IFNs) drive the formation of STAT1-STAT2 heterodimers, which then associate with the DNA-binding interferon regulatory protein 9 (IRF9) to form in-

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STAT2 Is a Pervasive Cytokine Regulator due to Its Inhibition of STAT1 in Multiple Signaling Pathways

Cited by 54 publications

References 55 publications

Selective Activation of Type II Interferon Signaling by Zika Virus NS5 Protein

Selective Activation of Type II Interferon Signaling by Zika Virus NS5 Protein

Current prospects of type II interferon γ signaling and autoimmunity

Responses to Cytokines and Interferons that Depend upon JAKs and STATs

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