Fish IRF6 is a positive regulator of IFN expression and involved in both of the MyD88 and TBK1 pathways

Li, Shun; Lu, Long-Feng; Wang, Zhao‐Xi; Chen, Dandan; Zhang, Yong-An

doi:10.1016/j.fsi.2016.08.059

Cited by 30 publications

(13 citation statements)

References 38 publications

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“…In this study, we found that the downregulation of TLRs reduced the activation of TLR-MyD88 signaling pathway, accompanied by decreased secretion of downstream molecules such as IFNg1-2 and IL-10. TLR signaling pathway can induce the expression of a variety of pro-inflammatory factors, thereby triggering the inflammatory response of the fish, and producing a warning signal for the invasion of pathogens (Li et al 2016). Similar to IL-1β, TNF-α is a potent pro-inflammatory cytokine in early inflammatory events (Muire et al 2017).…”

Section: Discussionmentioning

confidence: 99%

CpG-ODN 2007 protects zebrafish against Vibrio vulnificus-induced infection

Chen

Zhang²,

S³

et al. 2019

Preprint

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Vibrio vulnificus (V. vulnificus) is an aquatic pathogen that can cause primary sepsis and soft tissue infection. CpG oligodeoxynucleotides (CpG-ODN) are a type of essential immunomodulators, which can trigger or enhance immune responses in mammals, fish, and humans. In this study, we evaluated the effect of CpG-ODN 2007 as a potential immunostimulant for zebrafish infected with V. vulnificus (FJ03-X2). Fish injected with the CpG-ODN 2007 showed lower mortality rate compared with the fish that did not receive treatment. The survival rates of CpG-ODN 2007-treated group and PBS-treated group were 85% and 57.9%, respectively. In addition, our in vitro results demonstrated that CpG-ODN 2007 can effectively reduce the toxicity of V. vulnificus (FJ03-X2) to zebrafish embryonic fibroblast (ZF4) cells. Furthermore, we assessed immune-related genes expression patterns in FJ03-X2 infected zebrafish or ZF4 cells with and without CpG-ODN 2007 treatment, such as TLRs and IL-1β. To sum up, our data indicated that CpG-ODN 2007 protects zebrafish against Vibrio vulnificus induced infection.

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Section: Discussionmentioning

confidence: 99%

CpG-ODN 2007 protects zebrafish against Vibrio vulnificus-induced infection

Chen

Zhang²,

S³

et al. 2019

Preprint

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“…More type I IFN members are found in fish than in mammals (which possess only IFNα and IFNβ), and the regulation patterns are more complicated. TBK1 is the upstream kinase of IRF3, IRF7, and even IRF6 (positive regulator of fish IFNs), displaying a powerful capacity to activate IFNs [44]; therefore, targeting TBK1 is more efficient for a virus than targeting each IRF. (2) TBK1 has multiple functions in hosts.…”

Section: Discussionmentioning

confidence: 99%

Grass Carp Reovirus (GCRV) Giving Its All to Suppress IFN Production by Countering MAVS-TBK1 Activation

Zhang

et al. 2019

Preprint

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As a crucial signaling pathway for interferon (IFN) production, the RIG-I-like receptor (RLR) axis is usually the host target of viruses to enhance viral infection. To date, though immune evasion methods to contrapose IFN production have been characterized for a series of terrestrial viruses, the strategies employed by fish viruses remain unclear. Here, we report that all grass carp reovirus (GCRV) proteins encoded by segments S1 to S11 interact with fish RLR factors, specifically for mitochondrial antiviral signaling protein-TANK-binding kinase 1 (MAVS-TBK1) signaling transduction, leading to decreased IFN expression. First, the GCRV viral proteins blunted the MAVS-induced expression of IFN but had little effect on TBK1-induced IFN expression. Subsequently, interestingly, co-immunoprecipitation experiments demonstrated that all GCRV viral proteins interacted with several RLR cascades, especially with TBK1. To further illustrate the mechanisms of these interactions between GCRV viral proteins and host RLRs, two of the viral proteins, NS79 (S4) and VP3 (S3), were selected as representative proteins for the study. The obtained data demonstrated that NS79 did not affect the stability of the host RLR protein, but was phosphorylated by gcTBK1, leading to the reduction of host substrate gcIRF3/7 phosphorylation. On the other hand, VP3 degraded gcMAVS and the degradation was significantly reversed by 3-MA. The biological effects of both NS79 and VP3 were consistently found to be related to the suppression of IFN expression and the promotion of viral evasion. Our findings shed light on the special evasion mechanism utilized by fish virus through IFN regulation, which might differ between fish and mammals. Author summaryThe RLR signaling pathway is crucial for IFN induction when host cells are infected with virus and RLR factors are targeted by virus. To date, the evasion mechanisms of fish viruses remain mysterious. In this study, we reveal that all 11 GCRV proteins interact with fish RLR factors and suppress the activation of MAVS-TBK1 signaling transduction, leading to the reduction of IFN expression. Two viral proteins were employed as examples to investigate the different evasion mechanisms of GCRV.These findings reveal the novel countermeasures used by fish virus to avoid the host IFN response.

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“…Currently, 11 members of the IRF family have been found in fish ( 38 ). Most IRFs can positively regulate IFN expression ( 39 ) and are divided into the positive regulators (IRF1, IRF3, IRF4, IRF5, IRF6, IRF7, IRF8, IRF9, and IRF11) and negative regulators (IRF2 and IRF10) according to the capacity of IFN regulation ( 40 – 45 ). However, in addition to regulating the expression of IFN, increasing evidence suggests that IRFs are also involved in the regulation of many innate signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

IRF3 Negatively Regulates Toll-Like Receptor-Mediated NF-κB Signaling by Targeting TRIF for Degradation in Teleost Fish

et al. 2018

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NF-κB signaling is tightly regulated and essential to innate and adaptive immune responses, its regulatory mechanism remains unclear in various organisms, especially teleosts. In this study, we reported that IRF3 can negatively regulate TRIF-mediated NF-κB signaling pathway. Overexpression of IRF3 can inhibit TRIF-mediated NF-κB signaling pathway. However, knockdown of IRF3 had an opposite effect. IRF3 can promote the degradation of TRIF protein in mammal and fish cells, but this effect could be inhibited by MG132 treatment. Furthermore, we found that the inhibitory effect of IRF3 primary depended on its IRF association domain domain. IRF3 is crucial for the polyubiquitination and proteasomal degradation of TRIF. Our findings indicate that IRF3 negatively regulates TLR-mediated NF-κB signaling pathway by targeting TRIF for ubiquitination and degradation. This study provides a novel evidence on the negative regulation of innate immune signaling pathways in teleost fish and thus might provide new insights into the regulatory mechanisms in mammals.

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Fish IRF6 is a positive regulator of IFN expression and involved in both of the MyD88 and TBK1 pathways

Cited by 30 publications

References 38 publications

CpG-ODN 2007 protects zebrafish against Vibrio vulnificus-induced infection

CpG-ODN 2007 protects zebrafish against Vibrio vulnificus-induced infection

Grass Carp Reovirus (GCRV) Giving Its All to Suppress IFN Production by Countering MAVS-TBK1 Activation

IRF3 Negatively Regulates Toll-Like Receptor-Mediated NF-κB Signaling by Targeting TRIF for Degradation in Teleost Fish

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