Viral Induction of the Zinc Finger Antiviral Protein Is IRF3-dependent but NF-κB-independent

Wang, Nan; Dong, Qi; Li, Jingjing; Jangra, Rohit K.; Fan, Meiyun; Brasier, Allan R.; Lemon, Stanley M.; Pfeffer, Lawrence M.; Li, Kui

doi:10.1074/jbc.m109.054486

Cited by 66 publications

(61 citation statements)

References 69 publications

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“…ZAP is an interferon-inducible host antiviral factor (1)(2)(3)34). In this report, we show that MHV-68 infection upregulates ZAP expression and that ZAP inhibits the expression of MHV-68 ORF64.…”

Section: Discussionmentioning

confidence: 51%

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ZAP Inhibits Murine Gammaherpesvirus 68 ORF64 Expression and Is Antagonized by RTA

Xuan

Gong

et al. 2013

J Virol

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bZinc finger antiviral protein (ZAP) is an interferon-inducible host antiviral factor that specifically inhibits the replication of certain viruses, including HIV-1 and Ebola virus. ZAP functions as a dimer formed through intermolecular interactions of its N-terminal tails. ZAP binds directly to specific viral mRNAs and inhibits their expression by repressing translation and/or promoting degradation of the target mRNA. ZAP is not a universal antiviral factor, since some viruses grow normally in ZAP-expressing cells. It is not fully understood what determines whether a virus is susceptible to ZAP. We explored the interaction between ZAP and murine gammaherpesvirus 68 (MHV-68), whose life cycle has latent and lytic phases. We previously reported that ZAP inhibits the expression of M2, which is expressed mainly in the latent phase, and regulates MHV-68 latency in cultured cells. Here, we report that ZAP inhibits the expression of ORF64, a tegument protein that is expressed in the lytic phase and is essential for lytic replication. MHV-68 infection induced ZAP expression. However, ZAP did not inhibit lytic replication of MHV-68. We provide evidence showing that the antiviral activity of ZAP is antagonized by MHV-68 RTA, a critical viral transactivator expressed in the lytic phase. We further show that RTA inhibits the antiviral activity of ZAP by disrupting the N-terminal intermolecular interaction of ZAP. Our results provide an example of how a virus can escape ZAP-mediated immunity.

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Section: Discussionmentioning

confidence: 51%

“…inc finger antiviral protein (ZAP) (also named Zc3hav1) is a type I interferon-inducible host factor that specifically inhibits the replication of certain viruses (1)(2)(3). Initially, ZAP was recovered as a host factor that confers resistance to the replication of murine leukemia virus (MLV) (4).…”

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confidence: 99%

ZAP Inhibits Murine Gammaherpesvirus 68 ORF64 Expression and Is Antagonized by RTA

Xuan

Gong

et al. 2013

J Virol

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“…1d). The promoter region of the ZAP gene contains ISRE/IRF-E elements 40 . We investigated if expression of ZAPS and ZAP are regulated via similar mechanisms.…”

Section: Parps Contribute To the Ifn Responsementioning

confidence: 99%

ZAPS is a potent stimulator of signaling mediated by the RNA helicase RIG-I during antiviral responses

et al. 2010

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Japan. 8 These authors contributed equally to this work. Correspondence should be addressed to A.T. (takaoka@igm.hokudai.ac.jp). At least three DExD/H-box RNA helicases 4,5 , RIG-I, MDA5 and LGP2 are included in the RLR family. RIG-I is a key PRR for the detection of positive-and negative-stranded RNA viruses in the cytoplasm of cells 6,7 , and plays an important role in triggering responses against many viruses, such as orthomyxovirus (influenza A virus) and paramyxovirus (measles, mumps, and Sendai virus (SeV)) families, hepatitis C virus (HCV), and Japanese encephalitis virus (JEV) 8 . 5'-triphosphate modifications of RNA (3pRNA) are essential for RIG-I recognition and activation 9,10 . Ligand-binding activates the ATPase activity of RIG-I to change its structural conformation 6 , which in turn enables RIG-I to interact through its N-terminal tandem caspase recruitment domain (CARD) with the adaptor protein MAVS (for mitochondrial antiviral signaling protein, also known as IPS-1, VISA, or Cardif) [11][12][13][14] . MAVS then initiates the activation of interferon (IFN)-regulatory factor (IRF) 3, IRF7 and NF-κB transcriptional pathways for the subsequent production of type I IFNs and inflammatory cytokines, which are crucial for activating innate immune responses to viral infection 6,15 . Given the important role of the RIG-I pathway in the antiviral innate response, the mechanisms regulating RIG-I activation represent a topic of intense research [16][17][18] .Poly(ADP-ribose) polymerases (PARPs), a superfamily with least 17 members, are known to regulate not only cell survival and cell death programs triggered by DNA 3 damage, but also other biological functions as well as pathological processes, such as inflammatory and degenerative diseases, in a manner dependent or independent of their PARP activity [19][20][21][22] . Several PARP-superfamily members have a direct regulatory effect on replication of certain viruses 19,20,22,23 RESULTS 4PARPs contribute to the IFN response To investigate the role of the PARP-superfamily members in nucleic acid induced innate immune responses, we selected some of the PARP-superfamily members known to be involved in microbial infection, inflammation and immunity: PARP-1, PARP-2, PARP-7, PARP-9, 23,[31][32][33][34]. We then examined whether they have the ability to enhance the induction of IFNB mRNA in HEK293T cells in response to stimulation with three different types of nucleic acids-3pRNA, poly(rI:rC) and poly(dA-dT)•poly(dA-dT) (named poly(dA:dT) hereafter).Among the protein tested, PARP-13 uniquely showed a marked enhancing effect on IFNB mRNA expression induced by stimulation with 3pRNA, poly(rI:rC) and poly(dA:dT) ( Fig. 1a), all of which are known to activate the RIG-I-mediated pathway in HEK293T cells 9,10,[35][36][37] . A weak increase in IFNB mRNA expression was also detected in cells expressing PARP-1, PARP-2 and PARP-9. PARP-13 exists in at least two isoforms 22,26,38 . The amino-terminal 254-amino acid fragment of the rat homologue, which corresponds to the N...

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“…ZAP is not a universal antiviral factor because it does not inhibit the replication of viruses such as poliovirus and yellow fever virus (5). Type I interferon treatment or viral infection up-regulates ZAP expression (4,6,7), and down-regulation of endogenous ZAP enhances the expression of HIV-1 (2), suggesting that ZAP is an antiviral effector in vivo.…”

mentioning

confidence: 99%

Glycogen Synthase Kinase 3β (GSK3β) Modulates Antiviral Activity of Zinc-finger Antiviral Protein (ZAP)

Sun¹,

Lv²,

Guo

et al. 2012

Journal of Biological Chemistry

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Background: Zinc-finger antiviral protein (ZAP) is a type I interferon-inducible host antiviral factor against certain viruses, including HIV-1 and Ebola virus. Results: Glycogen synthase kinase 3␤ (GSK3␤) phosphorylates ZAP, and inhibition of GSK3␤ reduces ZAP activity. Conclusion: GSK3␤ phosphorylation of ZAP modulates its antiviral activity. Significance: These findings help to better understand how the immune response is regulated.

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Viral Induction of the Zinc Finger Antiviral Protein Is IRF3-dependent but NF-κB-independent

Cited by 66 publications

References 69 publications

ZAP Inhibits Murine Gammaherpesvirus 68 ORF64 Expression and Is Antagonized by RTA

ZAP Inhibits Murine Gammaherpesvirus 68 ORF64 Expression and Is Antagonized by RTA

ZAPS is a potent stimulator of signaling mediated by the RNA helicase RIG-I during antiviral responses

Glycogen Synthase Kinase 3β (GSK3β) Modulates Antiviral Activity of Zinc-finger Antiviral Protein (ZAP)

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