The Nuclear Export Protein of H5N1 Influenza A Viruses Recruits Matrix 1 (M1) Protein to the Viral Ribonucleoprotein to Mediate Nuclear Export

Brunotte, Linda; Flies, Joe; Bolte, Hardin; Reuther, Peter; Vreede, Frank T.; Schwemmle, Martin

doi:10.1074/jbc.m114.569178

Cited by 60 publications

(48 citation statements)

References 42 publications

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“…Mutations in NES1 inhibit virus recovery by reverse genetics and strongly impede vRNP nuclear export 84 ; whereas mutations in NES2 do not abolish virus recovery but severely impair viral growth kinetics and reduce the rate of vRNP nuclear export in infected cells 85 . Although these observations provide strong evidence of a role for NEP in vRNP nuclear export, no direct interaction between full-length NEP and the vRNP complex has been established 83,86–89 . However, since NEP can interact directly with the M1 protein 86,90 , which in turn interacts with vRNPs 80 , a ‘daisy-chain model’ for influenza vRNP nuclear export has been proposed, whereby NEP acts as an adaptor between the CRM1 nuclear export pathway and M1-vRNP complexes (Figure 4).…”

Section: Nuclear Export Of Progeny Vrnpsmentioning

confidence: 73%

“…However, since NEP can interact directly with the M1 protein 86,90 , which in turn interacts with vRNPs 80 , a ‘daisy-chain model’ for influenza vRNP nuclear export has been proposed, whereby NEP acts as an adaptor between the CRM1 nuclear export pathway and M1-vRNP complexes (Figure 4). Recent data suggests that a more refined model – in which NEP simultaneously interacts with M1, the PB1 subunit of the vRNP-associated polymerase complex, and the CRM1 nuclear export receptor 89 – may be necessary to explain the mechanism of vRNP nuclear export; further work is needed to clarify this process. Additionally, whether NEP remains associated with vRNP complexes that have been transported to the cytoplasm is currently unknown.…”

Section: Nuclear Export Of Progeny Vrnpsmentioning

confidence: 99%

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At the centre: influenza A virus ribonucleoproteins

2014

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Influenza A viral ribonucleoprotein (vRNP) complexes comprise the eight genomic negative-sense RNAs, each bound to multiple copies of viral nucleoprotein and a trimeric viral polymerase complex. The influenza virus life cycle centres on the vRNPs, which in turn, rely on host cellular processes to perform functions necessary for the successful completion of the virus life cycle. Here, we review our current knowledge about vRNP trafficking within host cells and the function of these complexes in the context of the virus life cycle, highlighting how structure contributes to function and the critical interactions with host cell pathways, as well as the information gaps that remain. An improved understanding of how vRNPs use host cell pathways is essential to identify mechanisms of virus pathogenicity, host adaptation, and ultimately, new targets for antiviral intervention.

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Section: Nuclear Export Of Progeny Vrnpsmentioning

confidence: 73%

Section: Nuclear Export Of Progeny Vrnpsmentioning

confidence: 99%

At the centre: influenza A virus ribonucleoproteins

2014

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“…M2 protein mediates nuclear transport of virus ribonuclear protein complexes41. M2 protein has also been shown to alter membrane curvature and assist in the budding of the virus4243, therefore the observed reduction of M2 protein expression could lead to a diminished assembly and release of viral particles.…”

Section: Discussionmentioning

confidence: 99%

Broad-Range Antiviral Activity of Hydrogen Sulfide Against Highly Pathogenic RNA Viruses

Bazhanov

Escaffre

Freiberg

et al. 2017

Sci Rep

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Hydrogen sulfide is an important endogenous mediator that has been the focus of intense investigation in the past few years, leading to the discovery of its role in vasoactive, cytoprotective and anti-inflammatory responses. Recently, we made a critical observation that H2S also has a protective role in paramyxovirus infection by modulating inflammatory responses and viral replication. In this study we tested the antiviral and anti-inflammatory activity of the H2S slow-releasing donor GYY4137 on enveloped RNA viruses from Ortho-, Filo-, Flavi- and Bunyavirus families, for which there is no FDA-approved vaccine or therapeutic available, with the exception of influenza. We found that GYY4137 significantly reduced replication of all tested viruses. In a model of influenza infection, GYY4137 treatment was associated with decreased expression of viral proteins and mRNA, suggesting inhibition of an early step of replication. The antiviral activity coincided with the decrease of viral-induced pro-inflammatory mediators and viral-induced nuclear translocation of transcription factors from Nuclear Factor (NF)-kB and Interferon Regulatory Factor families. In conclusion, increasing cellular H2S is associated with significant antiviral activity against a broad range of emerging enveloped RNA viruses, and should be further explored as potential therapeutic approach in relevant preclinical models of viral infections.

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“…Alternatively, a recent study suggested that influenza polymerase can adopt an alternative configuration depending on which kind of viral RNA (vRNA or cRNA) is bound (Thierry et al, 2016). In addition, NEP was also found to directly interact with the viral polymerase associated with vRNPs, in an M1-dependent manner (Brunotte et al, 2014), leaving open the possibility of a direct interaction between NEP and the viral polymerase associated with cRNPs in navigating cRNP nuclear export. Further analysis will be required to fully understand the cRNP nuclear export process, as well as its biological functions in the cytosol.…”

Section: Discussionmentioning

confidence: 99%

Selective incorporation of vRNP into influenza A virions determined by its specific interaction with M1 protein

Chaimayo

Hayashi²,

Underwood³

et al. 2017

Virology

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Influenza A viruses contain eight single-stranded, negative-sense RNA segments as viral genomes in the form of viral ribonucleoproteins (vRNPs). During genome replication in the nucleus, positive-sense complementary RNPs (cRNPs) are produced as replicative intermediates, which are not incorporated into progeny virions. To analyze the mechanism of selective vRNP incorporation into progeny virions, we quantified vRNPs and cRNPs in the nuclear and cytosolic fractions of infected cells, using a strand-specific qRT-PCR. Unexpectedly, we found that cRNPs were also exported to the cytoplasm. This export was chromosome region maintenance 1 (CRM1)-independent unlike that of vRNPs. Although both vRNPs and cRNPs were present in the cytosol, viral matrix (M1) protein, a key regulator for viral assembly, preferentially bound vRNPs over cRNPs. These results indicate that influenza A viruses selectively uptake cytosolic vRNPs through a specific interaction with M1 during viral assembly.

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The Nuclear Export Protein of H5N1 Influenza A Viruses Recruits Matrix 1 (M1) Protein to the Viral Ribonucleoprotein to Mediate Nuclear Export

Cited by 60 publications

References 42 publications

At the centre: influenza A virus ribonucleoproteins

At the centre: influenza A virus ribonucleoproteins

Broad-Range Antiviral Activity of Hydrogen Sulfide Against Highly Pathogenic RNA Viruses

Selective incorporation of vRNP into influenza A virions determined by its specific interaction with M1 protein

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