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Novel Function of Bluetongue Virus NS3 Protein in Regulation of the MAPK/ERK Signaling Pathway
Copyright policy )American Society for MicrobiologyNovel Function of Bluetongue Virus NS3 Protein in Regulation of the MAPK/ERK Signaling Pathway
AbstractBluetongue virus (BTV) is an arbovirus transmitted by blood-feeding midges to a wide range of wild and domestic ruminants. In this report, we showed that BTV, through its virulence non-structural protein NS3 (BTV-NS3), is able to activate the MAPK/ERK pathway. In response to growth factors, the MAPK/ERK pathway activates cell survival, differentiation, proliferation and protein translation but can also lead to the production of several inflammatory cytokines. By combining immunoprecipitation of BTV-NS3 and mass spectrometry analysis from both BTV-infected and NS3-transfected cells, we identified the serine/threonine-protein kinase B-Raf (BRAF), a crucial player of the MAPK/ERK pathway, as a new cellular interactor of BTV-NS3. BRAF silencing led to a significant decrease of the MAPK/ERK activation by BTV supporting a model where BTV-NS3 interacts with BRAF to activate this signaling cascade. Furthermore, the intrinsic ability of BTV-NS3 to bind BRAF and activate the MAPK/ERK pathway is conserved throughout multiple serotypes/strains but appears to be specific to BTV compared to other members ofOrbivirusgenus. Inhibition of MAPK/ERK pathway with U0126 reduced viral titers, suggesting that BTV manipulates this pathway for its own replication. Therefore, the activation of the MAPK/ERK pathway by BTV-NS3 could benefit to BTV replication by promoting its own viral protein synthesis but could also explain the deleterious inflammation associated with tissue damages as already observed in severe cases of BT disease. Altogether, our data provide molecular mechanisms to explain the role of BTV-NS3 as a virulence factor and determinant of pathogenesis.ImportanceBluetongue Virus (BTV) is responsible of the non-contagious arthropod-borne disease Bluetongue (BT) transmitted to ruminants by blood-feeding midges. Despite the fact that BTV has been extensively studied, we still have little understanding of the molecular determinants of BTV virulence. In this report, we found that the virulence protein NS3 interacts with BRAF, a key component of the MAPK/ERK pathway. In response to growth factors, this pathway promotes cell survival, increases protein translation but also contributes to the production of inflammatory cytokines. We showed that BTV-NS3 enhances the MAPK/ERK pathway and this activation is BRAF-dependent. Our results demonstrate, at the molecular level, how a single virulence factor has evolved to target a cellular function to ensure its viral replication. On the other hand, our findings could also explain the deleterious inflammation associated with tissue damages as already observed in severe cases of BT disease.
Medical Subject Headings: viruses digestive system diseases biochemical phenomena, metabolism, and nutrition virus diseases
Microsoft Academic Graph classification: Proinflammatory cytokine Gene silencing Virulence MAPK/ERK pathway Virulence factor Kinase Immunoprecipitation Cell biology Viral replication Biology Interferon medicine.drug medicine NS3 EIF4E Phosphorylation Protein kinase A
Immunology, Insect Science, Microbiology, Virology, Virology & Molecular Biology, Interferons, MAP kinases, Molecular virus-host interactions, Reoviridae, Virulence factors, Virologie & Moleculaire Biologie, MAP kinases, Reoviridae, interferons, Molecular virus-host interactions, Virulence factors, Animals, Bluetongue, Bluetongue virus, Cell Line, DNA-Binding Proteins, Host-Pathogen Interactions, Humans, MAP Kinase Signaling System, Phosphorylation, Protein Binding, Protein Transport, Proto-Oncogene Proteins B-raf, Transcription Factors, Viral Nonstructural Proteins, Virus Replication, Pathogenesis and Immunity, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology
Immunology, Insect Science, Microbiology, Virology, Virology & Molecular Biology, Interferons, MAP kinases, Molecular virus-host interactions, Reoviridae, Virulence factors, Virologie & Moleculaire Biologie, MAP kinases, Reoviridae, interferons, Molecular virus-host interactions, Virulence factors, Animals, Bluetongue, Bluetongue virus, Cell Line, DNA-Binding Proteins, Host-Pathogen Interactions, Humans, MAP Kinase Signaling System, Phosphorylation, Protein Binding, Protein Transport, Proto-Oncogene Proteins B-raf, Transcription Factors, Viral Nonstructural Proteins, Virus Replication, Pathogenesis and Immunity, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology
Medical Subject Headings: viruses digestive system diseases biochemical phenomena, metabolism, and nutrition virus diseases
Microsoft Academic Graph classification: Proinflammatory cytokine Gene silencing Virulence MAPK/ERK pathway Virulence factor Kinase Immunoprecipitation Cell biology Viral replication Biology Interferon medicine.drug medicine NS3 EIF4E Phosphorylation Protein kinase A
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- École nationale vétérinaire d'Alfort France
- Department of BiochemistryH
- CITEB France
- Department of Virology
- Université Paris Diderot France
- Ecole Nationale Vétérinaire d'Alfort
- North-West University South Africa
- Department of Virology France
- Department of Biogeochemistry
- CIRTEM France
- Institut Pasteur France
- ECOLE NATIONALE VETERINAIRE
- Paris Diderot University France
AbstractBluetongue virus (BTV) is an arbovirus transmitted by blood-feeding midges to a wide range of wild and domestic ruminants. In this report, we showed that BTV, through its virulence non-structural protein NS3 (BTV-NS3), is able to activate the MAPK/ERK pathway. In response to growth factors, the MAPK/ERK pathway activates cell survival, differentiation, proliferation and protein translation but can also lead to the production of several inflammatory cytokines. By combining immunoprecipitation of BTV-NS3 and mass spectrometry analysis from both BTV-infected and NS3-transfected cells, we identified the serine/threonine-protein kinase B-Raf (BRAF), a crucial player of the MAPK/ERK pathway, as a new cellular interactor of BTV-NS3. BRAF silencing led to a significant decrease of the MAPK/ERK activation by BTV supporting a model where BTV-NS3 interacts with BRAF to activate this signaling cascade. Furthermore, the intrinsic ability of BTV-NS3 to bind BRAF and activate the MAPK/ERK pathway is conserved throughout multiple serotypes/strains but appears to be specific to BTV compared to other members ofOrbivirusgenus. Inhibition of MAPK/ERK pathway with U0126 reduced viral titers, suggesting that BTV manipulates this pathway for its own replication. Therefore, the activation of the MAPK/ERK pathway by BTV-NS3 could benefit to BTV replication by promoting its own viral protein synthesis but could also explain the deleterious inflammation associated with tissue damages as already observed in severe cases of BT disease. Altogether, our data provide molecular mechanisms to explain the role of BTV-NS3 as a virulence factor and determinant of pathogenesis.ImportanceBluetongue Virus (BTV) is responsible of the non-contagious arthropod-borne disease Bluetongue (BT) transmitted to ruminants by blood-feeding midges. Despite the fact that BTV has been extensively studied, we still have little understanding of the molecular determinants of BTV virulence. In this report, we found that the virulence protein NS3 interacts with BRAF, a key component of the MAPK/ERK pathway. In response to growth factors, this pathway promotes cell survival, increases protein translation but also contributes to the production of inflammatory cytokines. We showed that BTV-NS3 enhances the MAPK/ERK pathway and this activation is BRAF-dependent. Our results demonstrate, at the molecular level, how a single virulence factor has evolved to target a cellular function to ensure its viral replication. On the other hand, our findings could also explain the deleterious inflammation associated with tissue damages as already observed in severe cases of BT disease.