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

Li, Shun; Lu, Long-Feng; Wang, Zhao‐Xi; Lu, Xiaobing; Chen, Dandan; Nie, Pin; Zhang, Yongan

doi:10.1128/jvi.01381-16

Cited by 77 publications

(27 citation statements)

References 45 publications

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“…In a water living environment, aquatic viruses can spread more easily and cause higher mortality than land-based viruses. In previous studies, our lab has reported that GCRV VP41 protein (encoded by the S8 segment) as well as SVCV N and P proteins antagonize fish RLR factors to reduce host IFN production [41][42][43], highlighting the evasion mechanisms used by aquatic viruses. To date, precise information regarding both the fish IFN response to viruses and the pathogenesis of aquatic viruses is rare;…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

“…The phosphorylation of viral proteins has also been observed in aquatic viruses. For example, SVCV P protein can be phosphorylated by TBK1, which leads to the decline of IRF3 phosphorylation and IFN production [43]. However, the function of phosphorylated P protein in SVCV proliferation is still unknown.…”

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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“…Similar to piscine MAVS and MITA , piscine TBK1 is also targeted by viruses as a major negative regulatory target to decrease the IFN response and facilitate viral replication. Spring viremia of carp virus (SVCV) P protein functions as a decoy substrate for cellular TBK1, leading to the reduction of IRF3 phosphorylation and suppression of IFN expression [ 155 ]. In zebrafish ( D. rerio ), a TBK1-like transcript (TBK1L), containing an incomplete S_TKc domain and lacking UBL_TBK1_like domain, was cloned.…”

Section: Alternative Splicing and Immune Function Of Downstream Simentioning

confidence: 99%

Alternative Pre-mRNA Splicing in Mammals and Teleost Fish: A Effective Strategy for the Regulation of Immune Responses Against Pathogen Infection

Chang

Zhang

2017

IJMS

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Pre-mRNA splicing is the process by which introns are removed and the protein coding elements assembled into mature mRNAs. Alternative pre-mRNA splicing provides an important source of transcriptome and proteome complexity through selectively joining different coding elements to form mRNAs, which encode proteins with similar or distinct functions. In mammals, previous studies have shown the role of alternative splicing in regulating the function of the immune system, especially in the regulation of T-cell activation and function. As lower vertebrates, teleost fish mainly rely on a large family of pattern recognition receptors (PRRs) to recognize pathogen-associated molecular patterns (PAMPs) from various invading pathogens. In this review, we summarize recent advances in our understanding of alternative splicing of piscine PRRs including peptidoglycan recognition proteins (PGRPs), nucleotide binding and oligomerization domain (NOD)-like receptors (NLRs), retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) and their downstream signaling molecules, compared to splicing in mammals. We also discuss what is known and unknown about the function of splicing isoforms in the innate immune responses against pathogens infection in mammals and teleost fish. Finally, we highlight the consequences of alternative splicing in the innate immune system and give our view of important directions for future studies.

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“…Several studies demonstrated that fish also possess a functional RLR pathway. For example, fish RIG-I and MDA5 have been shown to intensively trigger IFN production (22)(23)(24); IRF3 and MITA can be phosphorylated by TBK1, and they display a powerful capacity to activate IFN (25)(26)(27)(28)(29)(30).…”

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confidence: 99%

“…6D, the phosphorylation of MITA caused by TBK1 was reduced dose dependently with the overexpression of VP41. In addition, our previous study demonstrated that IRF3 can also be phosphorylated by TBK1 (29). Next, it was worth investigating whether VP41 affects the TBK1-induced phosphorylation of IRF3.…”

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confidence: 99%

Grass Carp Reovirus VP41 Targets Fish MITA To Abrogate the Interferon Response

Wang

et al. 2017

J Virol

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Although fish possess an efficient interferon (IFN) system to defend against aquatic virus infection, grass carp reovirus (GCRV) still causes hemorrhagic disease in grass carp. To date, GCRV's strategy for evading the fish IFN response is still unknown. Here, we report that GCRV VP41 inhibits fish IFN production by suppressing the phosphorylation of mediator of IFN regulatory factor 3 (IRF3) activation (MITA). First, the activation of the IFN promoter (IFNpro) stimulated by mitochondrial antiviral signaling protein (MAVS) and MITA was decreased by the overexpression of VP41, whereas such activation induced by TANK-binding kinase 1 (TBK1) was not affected. Second, VP41 was colocalized in the cellular endoplasmic reticulum (ER) and associated with MITA. Furthermore, as a phosphorylation substrate of TBK1, VP41 significantly decreased the phosphorylation of MITA. Truncation assays indicated that the transmembrane (TM) region of VP41 was indispensable for the suppression of IFNpro activity. Finally, after infection with GCRV, VP41 blunted the transcription of host IFN and facilitated viral RNA synthesis. Taken together, our findings suggest that GCRV VP41 prevents the fish IFN response by attenuating the phosphorylation of MITA for viral evasion.IMPORTANCE MITA is thought to act as an adaptor protein to facilitate the phosphorylation of IRF3 by TBK1 upon viral infection, and it plays a critical role in innate antiviral responses. Here, we report that GCRV VP41 colocalizes with MITA at the ER and reduces MITA phosphorylation by acting as a decoy substrate of TBK1, thus inhibiting IFN production. These findings reveal GCRV's strategy for evading the host IFN response for the first time.KEYWORDS VP41, GCRV, immune evasion, MITA, interferon G rass carp reovirus (GCRV), a highly virulent pathogenic agent of fish, has caused severe epidemic outbreaks of hemorrhagic disease and resulted in tremendous mortality in grass carp (Ctenopharyngodon idella) (1). It is a double-stranded RNA (dsRNA) virus belonging to the genus Aquareovirus in the family Reoviridae (2). The genome consists of 11 segments (termed S1 to S11) encased in a multilayered icosahedral capsid shell (3, 4). Based on genomic and biological characteristics, the known GCRV strains can be clustered into three groups (group I to group III) (2). Moreover, a protein sequence comparison showed that the similarity among the three groups is less than 20%, so the functions of the encoded proteins are likely to be diverse (2). For instance, segment 8 of group I has been found to encode a clamping protein (VP6) that bridges the inner core with the outer shell (3). Segment 8 of group II GCRV has been predicted to encode a protein of approximately 41 kDa (VP41) with a hydrophobic ␣-helical transmembrane (TM) region at the N terminus (5). Amino acid sequence

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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

Cited by 77 publications

References 45 publications

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

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

Alternative Pre-mRNA Splicing in Mammals and Teleost Fish: A Effective Strategy for the Regulation of Immune Responses Against Pathogen Infection

Grass Carp Reovirus VP41 Targets Fish MITA To Abrogate the Interferon Response

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