Functions of the two zebrafish MAVS variants are opposite in the induction of IFN1 by targeting IRF7

Lu, Long-Feng; Li, Shun; Lu, Xiaobing; Zhang, Yong-An

doi:10.1016/j.fsi.2015.05.019

Cited by 30 publications

(22 citation statements)

References 44 publications

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“…The plasmids encoding rig-1-Nter and tbk1 in the pcDNA3.1(+) vector (Invitrogen) and the plasmids containing Dr-IFNw1-luc, Dr-IFNw2-luc, Dr-IFNw3-luc, Dr-IFNw4-luc, and EPC-IFN-luc in the pGL3-Basic vector (Promega) were constructed as described previously (36,37). The ISRE luciferase reporter construct (ISRE-luc) containing five ISRE motifs in a series and the pFR-luc reporter construct were purchased from Stratagene.…”

Section: Plasmid Construction and Reagentsmentioning

confidence: 99%

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Zebrafish foxo3b Negatively Regulates Antiviral Response through Suppressing the Transactivity of irf3 and irf7

Xing

Cai

Zhang

et al. 2016

The Journal of Immunology

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Forkhead box O (FOXO)3, a member of the FOXO family of transcription factors, plays key roles in various cellular processes, including development, longevity, reproduction, and metabolism. Recently, FOXO3 has also been shown to be involved in modulating the immune response. However, how FOXO3 regulates immunity and the underlying mechanisms are still largely unknown. In this study, we show that zebrafish (Danio rerio) foxo3b, an ortholog of mammalian FOXO3, is induced by polyinosinic-polycytidylic acid stimulation and spring viremia of carp virus (SVCV) infection. We found that foxo3b interacted with irf3 and irf7 to inhibit ifr3/irf7 transcriptional activity, thus resulting in suppression of SVCV or polyinosinic-polycytidylic acid–induced IFN activation. By suppressing expression of key antiviral genes, foxo3b negatively regulated the cellular antiviral response. Furthermore, upon SVCV infection, the expression of the key antiviral genes was significantly enhanced in foxo3b-null zebrafish larvae compared with wild-type larvae. Additionally, the replication of SVCV was inhibited in foxo3b-null zebrafish larvae, leading to a higher survival rate. Our findings suggest that by suppressing irf3/irf7 activity, zebrafish foxo3b negatively regulates the antiviral response, implicating the vital role of the FOXO gene family in innate immunity.

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Section: Plasmid Construction and Reagentsmentioning

confidence: 99%

“…Initially, we performed reporter assays by taking advantage of the ISRE reporter, a commonly used reporter for monitoring viral infection or poly(I:C) stimulation (37). As shown in Fig.…”

Section: Zebrafish Foxo3b Inhibits Svcv or Poly(i:c)-induced Ifn Actimentioning

confidence: 99%

Zebrafish foxo3b Negatively Regulates Antiviral Response through Suppressing the Transactivity of irf3 and irf7

Xing

Cai

Zhang

et al. 2016

The Journal of Immunology

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“…The plasmids encoding RIG-I-Nter, TBK1, and IRF7 in the pcDNA3.1(+) vector (Invitrogen) and the plasmids containing IFNw1pro-Luc, IFNw2pro-Luc, IFNw3pro-Luc, IFNw4pro-Luc, and NF-kB-Luc in the pGL3-Basic luciferase reporter vector (Promega) were constructed as described previously (31)(32)(33). The IFN-stimulated response element (ISRE) luciferase reporter construct (ISRE-Luc) containing five ISRE motifs in series was purchased from Stratagene.…”

Section: Plasmid Construction and Reagentsmentioning

confidence: 99%

“…Similar to mammals, it has been shown that zebrafish MAVS plays an important role in IFN activation, which can significantly decrease the probability of infection with SVCV (29). In the RLR pathway, the truncated splicing variant of MAVS blocked the IFN induction by RIG-I, indicating the position of MAVS in the signaling pathway is conserved (30,31). These results demonstrate that the defense mechanisms of fish against SVCV infection are similar to that of mammals, especially regarding IFN production being activated by MAVS.…”

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confidence: 97%

Spring Viremia of Carp Virus N Protein Suppresses Fish IFNφ1 Production by Targeting the Mitochondrial Antiviral Signaling Protein

et al. 2016

The Journal of Immunology

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For a virus to replicate efficiently, it must try and inhibit host IFN expression because IFN is an important host defense at early stages after viral infection. For aquatic viruses, the mechanisms used to escape the hosts IFN system are still unclear. In this study, we show that the N protein of spring viremia of carp virus (SVCV) inhibits zebrafish IFNφ1 production by degrading the mitochondrial antiviral signaling protein (MAVS). First, the upregulation of IFNφ1 promoter activity stimulated by polyinosinic:polycytidylic acid, retinoic acid–inducible gene I (RIG-I) or MAVS was suppressed by the SVCV infection. However, the upregulation by the downstream factor of the RIG-I–like receptor signaling pathway, TANK-binding kinase 1, was not affected. Notably, at the protein level, MAVS decreased remarkably when cells were infected with SVCV. Second, consistent with the result of the SVCV infection, overexpression of the N protein of SVCV blocked the IFNφ1 transcription activated by MAVS and downregulated MAVS expression at the protein level but not at the mRNA level. Further analysis demonstrated that the N protein targeted MAVS for K48-linked ubiquitination, which promoted the degradation of MAVS. These data indicated that fish MAVS could be degraded by the N protein of SVCV through the ubiquitin-proteasome pathway. To our knowledge, this is the first article of a fish RIG-I–like receptor pathway interfered by an aquatic virus in an ubiquitin-proteasome manner, suggesting that immune evasion of a virus also exists in lower vertebrates.

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“…IFN-1pro and IFN-3pro luciferase reporter plasmids (IFN1pro-Luc or IFN3pro-Luc) and the expression plasmids for Flag-tagged MAVS, MITA, and TBK1 were described previously (25)(26)(27). All constructs were confirmed by DNA sequencing.…”

Section: Cells and Virusesmentioning

confidence: 99%

The P Protein of Spring Viremia of Carp Virus Negatively Regulates the Fish Interferon Response by Inhibiting the Kinase Activity of TANK-Binding Kinase 1

Wang

et al. 2016

J Virol

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Spring viremia of carp virus (SVCV) is an efficient pathogen causing high mortality in the common carp. Fish interferon (IFN) is a powerful cytokine enabling host cells to establish an antiviral response; therefore, the strategies that SVCV uses to avoid the cellular IFN response were investigated. Here, we report that the SVCV P protein is phosphorylated by cellular TANK-binding kinase 1 (TBK1), which decreases IFN regulatory factor 3 (IRF3) phosphorylation and suppresses IFN production. First, overexpression of P protein inhibited the IFN promoter activation induced by SVCV and the IFN activity activated by the mitochondrial antiviral signaling protein (MAVS) although TBK1 activity was not blocked by P protein. Second, P protein colocalized and interacted with TBK1. Dominant negative experiments suggested that the TBK1 N-terminal kinase domain interacted with P protein and was essential for P protein and IRF3 phosphorylation. Finally, P protein overexpression reduced the IRF3 phosphorylation activated by TBK1 and reduced host cellular ifn transcription. Collectively, our data demonstrated that the SVCV P protein is a decoy substrate for the host phosphokinase TBK1, preventing IFN production and facilitating SVCV replication. IMPORTANCETBK1 is a pivotal phosphokinase that activates host IFN production to defend against viral infection; thus, it is a potential target for viruses to negatively regulate IFN response and facilitate viral evasion. We report that the SVCV P protein functions as a decoy substrate for cellular TBK1, leading to the reduction of IRF3 phosphorylation and suppression of IFN expression. These findings reveal a novel immune evasion mechanism of SVCV. In aquatic viruses, spring viremia of carp virus (SVCV) belongs to the genus Vesiculovirus of the family Rhabdoviridae and causes significant mortality in the common carp (Cyprinus carpio) (1). Regarding its genome structure, SVCV encodes an ϳ11-kb negative-sense, single-stranded RNA that encodes five proteins in the following order (3= to 5=): nucleoprotein (N), phosphoprotein (P), matrix protein (M), glycoprotein (G), and viral RNA-dependent RNA polymerase (L) (2-4). The roles of these proteins in the replication and proliferation of rhabdovirus have been explored. N protein associates with viral RNA to form the nucleocapsid during viral assembly. M protein participates in the assembly and budding of virus, and G protein is involved in viral endocytosis. Moreover, as a phosphoprotein, the P protein is involved in several viral replication and assembly processes. As an example, the functional phosphorylated P protein interacts with the L protein to form a viral polymerase complex that interacts with the RNA template. In addition, the P protein also maintains the N protein in a soluble, encapsidation-competent form (1, 5).In host cells, viral RNAs can be recognized by the cellular immune system, triggering an antiviral response (6). In the cytoplasm, RIG-I-like receptors (RLRs), including RIG-I and MDA5, are the major pattern-recognition...

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Functions of the two zebrafish MAVS variants are opposite in the induction of IFN1 by targeting IRF7

Cited by 30 publications

References 44 publications

Zebrafish foxo3b Negatively Regulates Antiviral Response through Suppressing the Transactivity of irf3 and irf7

Zebrafish foxo3b Negatively Regulates Antiviral Response through Suppressing the Transactivity of irf3 and irf7

Spring Viremia of Carp Virus N Protein Suppresses Fish IFNφ1 Production by Targeting the Mitochondrial Antiviral Signaling Protein

The P Protein of Spring Viremia of Carp Virus Negatively Regulates the Fish Interferon Response by Inhibiting the Kinase Activity of TANK-Binding Kinase 1

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