Novel function of Bleutongue Virus NS3 Protein in Regulation of the MAPK/ERK Signaling Pathway

Cindy Kundlacz, Marie Pourcelot, Aurore Fablet, Rayane Amaral Da Silva Moraes, Thibaut Leger, Bastien Morlet, Cyril Viarouge, C. Sailleau, Mathilde Turpaud, Axel Gorlier, Emmanuel Breard, S. Lecollinet, P.A. van Rijn, Stephan Zientara, Damien Vitour*, Gregory Caignard

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

15 Citations (Scopus)


Bluetongue 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 nonstructural protein NS3 (BTV-NS3), is able to activate the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway, as assessed by phosphorylation levels of ERK1/2 and the translation initiation factor eukaryotic translation initiation factor 4E (eIF4E). 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 in the MAPK/ERK pathway, as a new cellular interactor of BTV-NS3. BRAF silencing led to a significant decrease in the MAPK/ERK activation by BTV, supporting a model wherein BTV-NS3 interacts with BRAF to activate this signaling cascade. This positive regulation acts independently of the role of BTV-NS3 in counteracting the induction of the alpha/beta interferon response. 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 of Orbivirus genus. Inhibition of MAPK/ERK pathway with U0126 reduced viral titers, suggesting that BTV manipulates this pathway for its own replication. Altogether, our data provide molecular mechanisms that unravel a new essential function of NS3 during BTV infection.
Original languageEnglish
Article numbere00336-19
Number of pages17
JournalJournal of Virology
Issue number16
Publication statusPublished - Aug 2019


  • Interferons
  • MAP kinases
  • Molecular virus-host interactions
  • Reoviridae
  • Virulence factors


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