Zika Virus Non-structural Protein 4A Blocks the RLR-MAVS Signaling

Ma, Jingyun; Ketkar, Harshada; Geng, Tingting; Lo, Emily J.; Wang, Leilei; Xi, Jing; Sun, Qiangming; Zhang, Zhu; Cui, Yudong; Yang, Long; Wang, Penghua

doi:10.3389/fmicb.2018.01350

Cited by 97 publications

(104 citation statements)

References 52 publications

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“…However, to date, knowledge about the immune evasion strategies of NNV is very limited. Increasing evidence has shown that viruses have evolved a wide variety of mechanisms to evade the host immune systems through interfering with the RLR signaling [3,24]. Several studies have exhibited the relationship between viral infection-induced miRNAs and RLRs signaling pathway, and demonstrated many miRNAs functioned as negative regulators of RLRs signaling pathway during viral infection.…”

Section: Discussionmentioning

confidence: 99%

MiR-202-5p Inhibits RIG-I-Dependent Innate Immune Responses to RGNNV Infection by Targeting TRIM25 to Mediate RIG-I Ubiquitination

Liu

Jin

Zhang

et al. 2020

Viruses

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The RIG-I-like receptors (RLRs) signaling pathway is essential for inducing type I interferon (IFN) responses to viral infections. Meanwhile, it is also tightly regulated to prevent uncontrolled immune responses. Numerous studies have shown that microRNAs (miRNAs) are essential for the regulation of immune processes, however, the detailed molecular mechanism of miRNA regulating the RLRs signaling pathway remains to be elucidated. Here, our results showed that miR-202-5p was induced by red spotted grouper nervous necrosis virus (RGNNV) infection in zebrafish. Overexpression of miR-202-5p led to reduced expression of IFN 1 and its downstream antiviral genes, thus facilitating viral replication in vitro. In comparison, significantly enhanced levels of IFN 1 and antiviral genes and significantly low viral burden were observed in the miR-202-5p-/- zebrafish compared to wild type zebrafish. Subsequently, zebrafish tripartite motif-containing protein 25 (zbTRIM25) was identified as a target of miR-202-5p in both zebrafish and humans. Ectopic expression of miR-202-5p suppressed zbTRIM25-mediated RLRs signaling pathway. Furthermore, we showed that miR-202-5p inhibited zbTRIM25-mediated zbRIG-I ubiquitination and activation of IFN production. In conclusion, we demonstrate that RGNNV-inducible miR-202-5p acts as a negative regulator of zbRIG-I-triggered antiviral innate response by targeting zbTRIM25. Our study reveals a novel mechanism for the evasion of the innate immune response controlled by RGNNV.

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Section: Discussionmentioning

confidence: 99%

MiR-202-5p Inhibits RIG-I-Dependent Innate Immune Responses to RGNNV Infection by Targeting TRIM25 to Mediate RIG-I Ubiquitination

Liu

Jin

Zhang

et al. 2020

Viruses

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“…Notably, some studies indicate that ZIKV is a weaker inducer of type I IFN, as it failed to activate a quick and robust innate immune response, especially compared with other RNA viruses or mimetic reagents, such as Sendai virus (SeV) or RNA synthetic analog polyinosinic:polycytidylic acid [poly(I:C)] (24). Recently, some progress has been made in understanding the immune escape mechanisms of ZIKV (25)(26)(27). Yet despite these findings, for ZIKV, virus proteins responsible for the immune escape and their molecular mechanisms are not fully elucidated.…”

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confidence: 99%

Zika virus circumvents host innate immunity by targeting the adaptor proteins MAVS and MITA

Dai

et al. 2019

FASEB j.

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Recently, Zika virus (ZIKV) has generated extraordinary concern because of its severe neurotoxicity. Disturbingly, there is no vaccine or specific drug to prevent or treat the diseases caused by ZIKV infection. Thus, it is extremely urgent to characterize the pathogenesis of ZIKV. It has been documented that ZIKV can evade antiviral responses of host cells. Here, we demonstrate that ZIKV strain SZ‐WIV01 down‐regulates the production of type I IFN and IFN‐stimulated genes along with the expression of mitochondrial antiviral signaling protein (MAVS) and mediator of IFN regulatory factor 3 activation (MITA). In the mechanism, ZIKV nonstructural (NS) 3 and NS2B3 negatively regulate IFN‐related retinoic acid‐inducible gene I‐like receptor signaling pathway by targeting MAVS and MITA, respectively. Overexpression of ZIKV NS3 and NS2B3 dramatically inhibits expression of IFN‐β. ZIKV NS3 interacts with MAVS, and NS2B3 interacts with MITA, which catalyzes K48‐linked polyubiquitination of MAVS and MITA for degradation. Further investigations suggest that ZIKV NS2B3 impairs polyinosinicpolycytidylic acid‐triggered K63‐linked polyubiquitination of MITA, thereby subverting the activation of downstream sensors. Our study reveals an undiscovered mechanism for ZIKV to escape the innate immune response, providing new insights into clinical study of vaccines or effective drugs.—Li, W., Li, N., Dai, S., Hou, G., Guo, K., Chen, X., Yi, C., Liu, W., Deng, F., Wu, Y., Cao, X. Zika virus circumvents host innate immunity by targeting the adaptor proteins MAVS and MITA. FASEB J. 33, 9929–9944 (2019). http://www.fasebj.org

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“…Since RAB1B positively regulated induction of IFN-β, we hypothesized that it would also be required for antiviral responses driven by IFN. Therefore, we tested if loss of RAB1B resulted in higher levels of viral infection during Zika virus (ZIKV) infection, a virus known to be susceptible to type I IFN (21). We treated Huh7 cells with either an siRNA to RAB1B or control, infected these cells with ZIKV (multiplicity of infection (MOI) 0.01), and then 48 hours later measured the production of infectious ZIKV particles in the supernatant using a focus-forming assay.…”

Section: Resultsmentioning

confidence: 99%

RAB1B interacts with TRAF3 to promote antiviral innate immunity

Beachboard

Park

Vijayan

et al. 2019

Preprint

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Nucleic acid-based antiviral innate immunity activates a signaling cascade that induces type I and type III interferons (IFNs), and other cytokines. This signaling, which is highly regulated, is initiated by pattern recognition receptors, such as RIG-I, that sense viral RNA and then signal to the adaptor protein, MAVS. This adaptor protein then recruits additional signaling proteins, including TRAF3 and TBK1, to form a signaling complex that results in IRF3 activation for transcriptional induction of IFN. Here, we show that the GTPase trafficking protein RAB1B positively regulates RIG-I signaling to promote IFN-β induction and the antiviral response. Overexpression of RAB1B increases RIG-I-mediated signaling to IFN-β, while deletion results in reduced signaling of this pathway. Additionally, this loss of RAB1B results in a dampened antiviral response, as Zika virus infection is enhanced in the absence of RAB1B. Importantly, we identified the mechanism of RAB1B action by determining that it

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Zika Virus Non-structural Protein 4A Blocks the RLR-MAVS Signaling

Cited by 97 publications

References 52 publications

MiR-202-5p Inhibits RIG-I-Dependent Innate Immune Responses to RGNNV Infection by Targeting TRIM25 to Mediate RIG-I Ubiquitination

MiR-202-5p Inhibits RIG-I-Dependent Innate Immune Responses to RGNNV Infection by Targeting TRIM25 to Mediate RIG-I Ubiquitination

Zika virus circumvents host innate immunity by targeting the adaptor proteins MAVS and MITA

RAB1B interacts with TRAF3 to promote antiviral innate immunity

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