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Viperin targets flavivirus virulence by inducing assembly of non-infectious capsid particles
Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). (Anna Överby Wernstedt)
Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). (Anna Överby Wernstedt)
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
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2018 (English)In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 92, no 1, article id e01751-17Article in journal (Refereed) Published
Abstract [en]

Efficient antiviral immunity requires interference with virus replication at multiple layers targeting diverse steps in the viral life cycle. Here we describe a novel flavivirus inhibition mechanism that results in interferon-mediated obstruction of tick-borne encephalitis virus particle assembly, and involves release of malfunctional membrane associated capsid (C) particles. This mechanism is controlled by the activity of the interferon-induced protein viperin, a broad spectrum antiviral interferon stimulated gene. Through analysis of the viperin-interactome, we identified the Golgi Brefeldin A resistant guanine nucleotide exchange factor 1 (GBF1), as the cellular protein targeted by viperin. Viperin-induced antiviral activity as well as C-particle release was stimulated by GBF1 inhibition and knock down, and reduced by elevated levels of GBF1. Our results suggest that viperin targets flavivirus virulence by inducing the secretion of unproductive non-infectious virus particles, by a GBF1-dependent mechanism. This yet undescribed antiviral mechanism allows potential therapeutic intervention.Importance The interferon response can target viral infection on almost every level, however, very little is known about interference of flavivirus assembly. Here we show that interferon, through the action of viperin, can disturb assembly of tick-borne encephalitis virus. The viperin protein is highly induced after viral infection and exhibit broad-spectrum antiviral activity. However, the mechanism of action is still elusive and appear to vary between the different viruses, indicating that cellular targets utilized by several viruses might be involved. In this study we show that viperin induce capsid particle release by interacting and inhibiting the function of the cellular protein Golgi Brefeldin A resistant guanine nucleotide exchange factor 1 (GBF1). GBF1 is a key protein in the cellular secretory pathway and essential in the life cycle of many viruses, also targeted by viperin, implicating GBF1 as a novel putative drug target.

Place, publisher, year, edition, pages
American Society of Microbiology , 2018. Vol. 92, no 1, article id e01751-17
Keywords [en]
COPI,  COPII,  GBF1,  assembly,  capsid,  flavivirus,  interferon,  tick-borne encephalitis virus,  viperi
National Category
Microbiology in the medical area Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-143054DOI: 10.1128/JVI.01751-17ISI: 000417922700037PubMedID: 29046456OAI: oai:DiVA.org:umu-143054DiVA, id: diva2:1166248
Funder
Swedish Research Council, 2011-2795Swedish Foundation for Strategic Research , ICA10-0059, FFL12-0089, FFL09-0181Available from: 2017-12-14 Created: 2017-12-14 Last updated: 2018-06-09Bibliographically approved

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Vonderstein, KirstinNilsson, EmmaNygård Skalman, LarsUpadhyay, ArunkumarPasto, JennyLundmark, RichardÖverby, Anna K.
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VirologyMolecular Infection Medicine Sweden (MIMS)Department of Medical Biochemistry and BiophysicsDepartment of Integrative Medical Biology (IMB)
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