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Novel Function of Bluetongue Virus NS3 Protein in Regulation of The bioRxiv preprint doi: https://doi.org/10.1101/562421; this version posted February 27, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 Novel Function of Bluetongue Virus NS3 Protein in Regulation of 2 the MAPK/ERK Signaling Pathway 3 4 Authors: Cindy Kundlacz1, Marie Pourcelot1, Aurore Fablet1, Rayane Amaral Da Silva 5 Moraes1, Thibaut Léger2, Bastien Morlet2, Cyril Viarouge1, Corinne Sailleau1, Mathilde 6 Turpaud1, Axel Gorlier1, Emmanuel Breard1, Sylvie Lecollinet1, Piet A. van Rijn3,4, Stephan 7 Zientara1, Damien Vitour1,Ψ#, Grégory Caignard1,Ψ# 8 9 Affiliations: UMR VIROLOGIE, INRA, École Nationale Vétérinaire d’Alfort, ANSES, 10 Université Paris-Est, Maisons-Alfort, 94700, France1. Mass spectrometry and proteomics 11 facility, Jacques Monod Institute, UMR 7592, Paris Diderot University, CNRS, Sorbonne Paris 12 Cité, F-75205, Paris Cedex 13, France2. Department of Virology, Wageningen Bioveterinary 13 Research, PO box 65, 8200 AB, Lelystad, The Netherlands3. Department of Biochemistry, 14 Centre for Human Metabolomics, North-West University, South Africa4. These authors 15 contributed equally to this workΨ. 16 17 # Corresponding authors: 18 Grégory Caignard, UMR VIROLOGIE, Maisons-Alfort, France 19 Email: [email protected]; Phone: 33-(1)-43-96-73-75 20 Damien Vitour, UMR VIROLOGIE, Maisons-Alfort, France 21 Email: [email protected]; Phone: 33-(1)-43-96-73-30 22 23 Running title: BTV-NS3 binds BRAF and activates the MAPK/ERK pathway. 24 Abstract: 242 words. Text: 5,651 words. 1 bioRxiv preprint doi: https://doi.org/10.1101/562421; this version posted February 27, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 25 Abstract 26 27 Bluetongue virus (BTV) is an arbovirus transmitted by blood-feeding midges to a wide 28 range of wild and domestic ruminants. In this report, we showed that BTV, through its virulence 29 non-structural protein NS3 (BTV-NS3), is able to activate the MAPK/ERK pathway. In 30 response to growth factors, the MAPK/ERK pathway activates cell survival, differentiation, 31 proliferation and protein translation but can also lead to the production of several inflammatory 32 cytokines. By combining immunoprecipitation of BTV-NS3 and mass spectrometry analysis 33 from both BTV-infected and NS3-transfected cells, we identified the serine/threonine-protein 34 kinase B-Raf (BRAF), a crucial player of the MAPK/ERK pathway, as a new cellular interactor 35 of BTV-NS3. BRAF silencing led to a significant decrease of the MAPK/ERK activation by 36 BTV supporting a model where BTV-NS3 interacts with BRAF to activate this signaling 37 cascade. Furthermore, the intrinsic ability of BTV-NS3 to bind BRAF and activate the 38 MAPK/ERK pathway is conserved throughout multiple serotypes/strains but appears to be 39 specific to BTV compared to other members of Orbivirus genus. Inhibition of MAPK/ERK 40 pathway with U0126 reduced viral titers, suggesting that BTV manipulates this pathway for its 41 own replication. Therefore, the activation of the MAPK/ERK pathway by BTV-NS3 could 42 benefit to BTV replication by promoting its own viral protein synthesis but could also explain 43 the deleterious inflammation associated with tissue damages as already observed in severe cases 44 of BT disease. Altogether, our data provide molecular mechanisms to explain the role of BTV- 45 NS3 as a virulence factor and determinant of pathogenesis. 2 bioRxiv preprint doi: https://doi.org/10.1101/562421; this version posted February 27, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 46 Importance 47 48 Bluetongue Virus (BTV) is responsible of the non-contagious arthropod-borne disease 49 Bluetongue (BT) transmitted to ruminants by blood-feeding midges. Despite the fact that BTV 50 has been extensively studied, we still have little understanding of the molecular determinants 51 of BTV virulence. In this report, we found that the virulence protein NS3 interacts with BRAF, 52 a key component of the MAPK/ERK pathway. In response to growth factors, this pathway 53 promotes cell survival, increases protein translation but also contributes to the production of 54 inflammatory cytokines. We showed that BTV-NS3 enhances the MAPK/ERK pathway and 55 this activation is BRAF-dependent. Our results demonstrate, at the molecular level, how a 56 single virulence factor has evolved to target a cellular function to ensure its viral replication. 57 On the other hand, our findings could also explain the deleterious inflammation associated with 58 tissue damages as already observed in severe cases of BT disease. 3 bioRxiv preprint doi: https://doi.org/10.1101/562421; this version posted February 27, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 59 Introduction 60 61 Bluetongue Virus (BTV) is the etiologic agent of the non-contagious arthropod-borne 62 disease Bluetongue (BT) transmitted to ruminants by blood-feeding midges of the genus 63 Culicoides. It belongs to the Orbivirus genus within the Reoviridae family, with 27 serotypes 64 currently identified (1) and at least 6 putative new serotypes (2–7). BTV infects a broad 65 spectrum of wild and domestic ruminants even if sheep are the most sensitive species to the 66 disease. During the 20th century BTV was principally circumscribed to tropical and subtropical 67 geographical areas (8). In 2006, BTV serotype 8 (BTV-8, strain 2006) emerged in Northern 68 Europe (9) from which it rapidly spread to Central and Western Europe, causing significant 69 economic losses (mortality, morbidity, reduced production and restrictions in trade of 70 ruminants). Despite the fact that a high vaccination coverage has been achieved across many 71 European countries allowing the control of the BT disease, BTV outbreaks are still a major 72 concern for the World Organisation for Animal Health (OIE), particularly in Europe (1). 73 Clinical signs include hemorrhagic fever, ulcer in the oral cavity and upper gastrointestinal 74 tract, necrosis of the skeletal and cardiac muscle and oedema of the lungs (10). These 75 variabilities in its host range and clinical manifestations are due to several factors related both 76 to the infected hosts and the viral serotypes and strains. 77 The BTV genome is composed of 10 double-stranded RNA (dsRNA) segments 78 encoding seven structural (VP1 to VP7) and five, or possibly six, non-structural (NS1 to NS4, 79 NS3A and possibly NS5) proteins (11–13). The BT virion is an icosahedral particle organized 80 as a triple-layered capsid. Viral genomic segments are associated with replication complexes 81 containing VP1 (RNA-dependent RNA polymerase), VP4 (capping enzyme including 82 methyltransferase), VP6 (RNA-dependent ATPase and helicase) and enclosed by VP3 83 (subcore) and VP7 (core) (14). Cell attachment and viral entry involve the two structural 4 bioRxiv preprint doi: https://doi.org/10.1101/562421; this version posted February 27, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 84 proteins of the outer capsid VP5 and the most variable of BTV protein VP2 representing the 85 main target of neutralizing antibodies and determines the serotype specificity (15, 16). Non- 86 structural proteins contribute to the control of BTV replication (17), viral protein synthesis (18), 87 maturation and export from the infected cells (19–23). Initially described for NS4, NS3 has also 88 been shown to counteract the innate immune response, and in particular the type I interferon 89 (IFN-α/β) pathway (13, 24, 25). 90 NS3 is encoded by the segment 10 and expressed as two isoforms, NS3 and NS3A, the 91 latter being translated from an second in-frame start codon by which the first N-terminal 13 92 amino acids residues are lacking (26). NS3 proteins are glycoproteins that promote viral release 93 either through its viroporin activity (20) or by budding. This latter implies interactions between 94 NS3 and outer capsid VP2/VP5 proteins (27), and cellular proteins involved in the pathway of 95 endosomal sorting complexes required for transport (ESCRT) (TSG101 and NEDD4-like 96 ubiquitin ligase) and the calpactin light chain p11 (23, 28, 29). Altogether, these reports provide 97 molecular basis of the multifunctional role of BTV-NS3 as a virulence factor and determinant 98 of pathogenesis as also illustrated by other in vivo studies using BTV monoreassortants and 99 NS3/NS3A knockout mutants (30–32). 100 Many viruses can modulate and hijack signaling pathways related to the mitogen- 101 activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway for more 102 efficient replication (33). In response to extracellular stimuli such as growth factors, several 103 downstream components of the MAPK/ERK pathway including RAS, RAF, MEK1/2 and 104 ERK1/2 are successively activated. Then, ERK1/2 directly or indirectly regulates transcription 105 factors (e.g. Elk1) involved in cell proliferation, differentiation and survival (34, 35) but also 106 cellular factors that control mRNA translation like eukaryotic initiation factor 4E (eIF4E) (36). 107 In 2010, Mortola and colleagues were the first to show the modulation, as activation, of the 108 MAPK/ERK pathway by BTV (37). In contrast to this finding, other studies demonstrated that 5 bioRxiv preprint doi: https://doi.org/10.1101/562421; this version posted February 27, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder.
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