Viperin Restricts Zika Virus and Tick-Borne Encephalitis Virus Replication by Targeting NS3 for Proteasomal Degradation

Panayiotou, Christakis; Lindqvist, Richard; Kurhade, Chaitanya; Vonderstein, Kirstin; Pasto, Jenny; Edlund, Karin; Upadhyay, Arunkumar S.; Överby, Anna K.

doi:10.1128/jvi.02054-17

Cited by 94 publications

(129 citation statements)

References 41 publications

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“…It has since been shown to inhibit viruses of several classes including the flaviviruses DENV, WNV, tick-borne encephalitis virus (TBEV) and ZIKV, as well as influenza, CMV and hepatitis C (HCV) (Wang, Hinson et al 2007, Jiang, Weidner et al 2010, Szretter, Brien et al 2011, Wang, Wu et al 2012, Helbig, Carr et al 2013, Upadhyay, Vonderstein et al 2014, Van der Hoek, Eyre et al 2017, Panayiotou, Lindqvist et al 2018). Multiple mechanisms have been proposed to account for viperin antiviral activity.…”

Section: Discussionmentioning

confidence: 99%

“…Viperin localizes to the ER membrane and is then transported to lipid droplets that serve as lipid storage sites and assembly platforms for viruses. Several antiviral host proteins localize to lipid droplets including viperin which is reported to interact ZIKV NS3 (Panayiotou, Lindqvist et al 2018). Viperin inhibits farnesyl diphosphate synthase, an essential enzyme in isoprenoid biosynthesis, causing disruption of cholesterol-rich lipid rafts results in a block to virus assembly and release (Wang, Hinson et al 2007, Nasr, Maddocks et al 2012).…”

Section: Discussionmentioning

confidence: 99%

“…In the replication complex, viperin may interact with NS5, the viral RNA-dependent RNA polymerase (RdRp) that synthesizes minus- and plus-strand RNA or could act through an intermediate host factor, as has been found for HCV (Helbig, Eyre et al 2011, Wang, Wu et al 2012). Viperin was recently shown to induce the proteasomal degradation of ZIKV NS3, a helicase required to unwind the double-stranded RNA (dsRNA) (Panayiotou, Lindqvist et al 2018) and to interact with DENV NS3 (Helbig, Carr et al 2013), interfering with early viral RNA synthesis.…”

Section: Discussionmentioning

confidence: 99%

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Toll-like receptor agonist R848 blocks Zika virus replication by inducing the antiviral protein viperin

2018

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Zika virus (ZIKV) is an emerging pathogen linked to neurological disorders for which there is currently no targeted therapy. To identify host innate immune response proteins that restrict ZIKV replication, we treated monocytes and macrophages with toll-like receptor (TLR) agonists. Of those tested, the TLR7/8 agonist R848 (resiquimod) was the most potent. RNA-seq analysis identified several genes strongly induced by R848 in monocytes. Testing of several of these for their ability to restrict ZIKV replication identified viperin, an interferon-induced gene active against several viruses. Transduction of microglial CHME3 cells with a viperin lentiviral expression vector rendered them resistant to ZIKV infection, preventing the synthesis of viral RNA and protein. CRISPR/Cas9 knock-out (KO) of viperin in macrophages relieved the block to infection, demonstrating that viperin is a major innate immune response protein able to block ZIKV replication. TLR agonists may be useful for the prophylactic or therapeutic treatment for ZIKV.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Toll-like receptor agonist R848 blocks Zika virus replication by inducing the antiviral protein viperin

2018

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“…Viral infection of organisms or cells is known to lead to the induction of over 200 different interferon‐stimulated genes (ISGs) as a part of the innate immune response . One ISG with known antiviral activity is viperin, which has been shown to be capable of inhibiting the replication of both RNA and DNA viruses following its interferon‐mediated induction . Viperin localizes to the membrane of the endoplasmic reticulum, viperin can interfere with multiple stages of the viral life cycle, disrupting processes such as assembly, maturation, budding, and release of viral particles .…”

Section: Introductionmentioning

confidence: 99%

Viperin inhibits classical swine fever virus replication by interacting with viral nonstructural 5A protein

Feng

Chen

et al. 2019

Journal of Medical Virology

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Classical swine fever virus (CSFV) is a single‐stranded RNA flavivirus that can cause serious diseases in porcine species, including symptoms of infarction, systemic hemorrhage, high fever, or depression. Viperin is an important interferon‐inducible antiviral gene that has been shown to inhibit CSFV, but the exact mechanisms by which it is able to do so remain poorly characterized. In the present study, we determined that CSFV infection led to viperin upregulation in PK‐15 cells (porcine kidney cell). When viperin was overexpressed in these cells, this markedly attenuated CSFV replication, with clear reductions in viral copy number after 12 to 48 hours postinfection. Immunofluorescence microscopy revealed that the viral NS5A protein colocalized with viperin in infected cells, and this was confirmed via confocal laser scanning microscopy using labeled versions of these proteins, and by co‐immunoprecipitation which confirmed that NS5A directly interacts with viperin. When NS5A was overexpressed, this inhibited the replication of CSFV, and we determined that the radical SAM domain and N‐terminal domain of viperin was critical for its ability to bind to NS5A, with the latter being most important for this interaction. Together, our in vitro results highlight a potential mechanism whereby viperin is able to inhibit CSFV replication. These results have the potential to assist future efforts to prevent or treat systemic CSFV‐induced disease, and may also offer more general insights into the antiviral role of viperin in innate immunity.

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“…An interesting strategy by DenV was reported where the viral protein NS5 stimulates proteasomal degradation of STAT2 and blocks type 1 IFN signalling and thus evades the host immune mechanisms [182]. Similarly selective degradation of NS3 (non-structural protein) of the Zika virus via proteasome mediated pathway was recently reported [183]. This proteasome dependant degradation of the viral protein was proposed as a strategy for the host antiviral mechanism.…”

Section: Host Ubiquitin Proteasome System (Ups)mentioning

confidence: 98%

Organelle dynamics and viral infections: at cross roads

Glingston

Deb

Kumar

et al. 2019

Microbes and Infection

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Viruses are obligate intracellular parasites of the host cells. A commonly accepted view is the requirement of internal membranous structures for various aspects of viral life cycle. Organelles enable favourable intracellular environment for several viruses. However, studies reporting organelle dynamics upon viral infections are scant. In this review, we aim to summarize and highlight modulations caused to various organelles upon viral infection or expression of its proteins.

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Viperin Restricts Zika Virus and Tick-Borne Encephalitis Virus Replication by Targeting NS3 for Proteasomal Degradation

Cited by 94 publications

References 41 publications

Toll-like receptor agonist R848 blocks Zika virus replication by inducing the antiviral protein viperin

Toll-like receptor agonist R848 blocks Zika virus replication by inducing the antiviral protein viperin

Viperin inhibits classical swine fever virus replication by interacting with viral nonstructural 5A protein

Organelle dynamics and viral infections: at cross roads

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