Orbivirus NS4 Proteins Play Multiple Roles to Dampen Cellular Responses

Author:

Mohd Jaafar Fauziah1ORCID,Belhouchet Mourad2,Monsion Baptiste1ORCID,Bell-Sakyi Lesley3ORCID,Mertens Peter P. C.4,Attoui Houssam1ORCID

Affiliation:

1. UMR1161 VIROLOGIE, INRAE, Ecole Nationale Vétérinaire d’Alfort, ANSES, Université Paris-Est, 94700 Maisons-Alfort, France

2. Division of Structural Biology, Henry Wellcome Building for Genomic Medicine, Oxford OX3 7BN, UK

3. Department of Infection Biology and Microbiomes, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, 146 Brownlow Hill, Liverpool L3 5RF, UK

4. One Virology, The Wolfson Centre for Global Virus Research, School of Veterinary Medicine and Science, University of Nottingham, Sutton Bonington Campus, Loughborough, Leicestershire LE12 5RD, UK

Abstract

Non-structural protein 4 (NS4) of insect-borne and tick-borne orbiviruses is encoded by genome segment 9, from a secondary open reading frame. Though a protein dispensable for bluetongue virus (BTV) replication, it has been shown to counter the interferon response in cells infected with BTV or African horse sickness virus. We further explored the functional role(s) of NS4 proteins of BTV and the tick-borne Great Island virus (GIV). We show that NS4 of BTV or GIV helps an E3L deletion mutant of vaccinia virus to replicate efficiently in interferon-treated cells, further confirming the role of NS4 as an interferon antagonist. Our results indicate that ectopically expressed NS4 of BTV localised with caspase 3 within the nucleus and was found in a protein complex with active caspase 3 in a pull-down assay. Previous studies have shown that pro-apoptotic caspases (including caspase 3) suppress type I interferon response by cleaving mediators involved in interferon signalling. Our data suggest that orbivirus NS4 plays a role in modulating the apoptotic process and/or regulating the interferon response in mammalian cells, thus acting as a virulence factor in pathogenesis.

Funder

European Commission H2020 research project PALE Blu

United Kingdom Biotechnology and Biological Sciences Research Council

Wellcome Trust

Publisher

MDPI AG

Subject

Virology,Infectious Diseases

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