Ubiquitination and deubiquitination of NP protein regulates influenza A virus RNA replication

Liao, Tsai‐Ling; Wu, Chung‐Yi; Su, Wu‐Chung; Jeng, King‐Song; Lai, Michael M. C.

doi:10.1038/emboj.2010.250

Cited by 111 publications

(125 citation statements)

References 50 publications

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“…However, this helicase is not restricted to the nucleus and partially redistributes to the cytoplasm in the presence of human MxA (98), which argues against the hypothesis that it could be responsible for the strict nuclear activity of the mouse Mx1 protein. Other potential bridging factors that bind to influenza virus vRNP components include nucleophosmin (99), CDK9 (100), USP11 (101), and Hsp90 (102,103). It is also possible that mouse Mx1 recognizes viral targets that adopt the right conformation only in the nucleus.…”

Section: Antiviral Activity Against Orthomyxoviridaementioning

confidence: 99%

Mx Proteins: Antiviral Gatekeepers That Restrain the Uninvited

Verhelst

Hulpiau

Saelens

2013

Microbiol Mol Biol Rev

255

178

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SUMMARY Fifty years after the discovery of the mouse Mx1 gene, researchers are still trying to understand the molecular details of the antiviral mechanisms mediated by Mx proteins. Mx proteins are evolutionarily conserved dynamin-like large GTPases, and GTPase activity is required for their antiviral activity. The expression of Mx genes is controlled by type I and type III interferons. A phylogenetic analysis revealed that Mx genes are present in almost all vertebrates, usually in one to three copies. Mx proteins are best known for inhibiting negative-stranded RNA viruses, but they also inhibit other virus families. Recent structural analyses provide hints about the antiviral mechanisms of Mx proteins, but it is not known how they can suppress such a wide variety of viruses lacking an obvious common molecular pattern. Perhaps they interact with a (partially) symmetrical invading oligomeric structure, such as a viral ribonucleoprotein complex. Such an interaction may be of a fairly low affinity, in line with the broad target specificity of Mx proteins, yet it would be strong enough to instigate Mx oligomerization and ring assembly. Such a model is compatible with the broad “substrate” specificity of Mx proteins: depending on the size of the invading viral ribonucleoprotein complexes that need to be wrapped, the assembly process would consume the necessary amount of Mx precursor molecules. These Mx ring structures might then act as energy-consuming wrenches to disassemble the viral target structure.

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Section: Antiviral Activity Against Orthomyxoviridaementioning

confidence: 99%

Mx Proteins: Antiviral Gatekeepers That Restrain the Uninvited

Verhelst

Hulpiau

Saelens

2013

Microbiol Mol Biol Rev

255

178

View full text Add to dashboard Cite

show abstract

“…Coexpression of UAP56 also did not influence the inhibition of the PB2-NP interaction by Mx1 (data not shown), suggesting that UAP56 is not directly involved in the activity of the Mx1 protein. Other cellular factors that might be involved include nucleophosmin (32), one of the importin-alpha isoforms (2, 10), CDK9 (52), USP11 (29), and Hsp90 (4,35,36), all of which have been shown to interact with PB2 and/or NP. Only a few proteins have been reported to interact with the Mx1 protein, and these interacting proteins are potential candidates as bridging factors (9).…”

Section: Discussionmentioning

confidence: 99%

Interferon-Inducible Protein Mx1 Inhibits Influenza Virus by Interfering with Functional Viral Ribonucleoprotein Complex Assembly

Verhelst

Parthoens

Schepens

et al. 2012

J Virol

197

168

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bMx1 is a GTPase that is part of the antiviral response induced by type I and type III interferons in the infected host. It inhibits influenza virus infection by blocking viral transcription and replication, but the molecular mechanism is not known. Polymerase basic protein 2 (PB2) and nucleoprotein (NP) were suggested to be the possible target of Mx1, but a direct interaction between Mx1 and any of the viral proteins has not been reported. We investigated the interplay between Mx1, NP, and PB2 to identify the mechanism of Mx1's antiviral activity. We found that Mx1 inhibits the PB2-NP interaction, and the strength of this inhibition correlated with a decrease in viral polymerase activity. Inhibition of the PB2-NP interaction is an active process requiring enzymatically active Mx1. We also demonstrate that Mx1 interacts with the viral proteins NP and PB2, which indicates that Mx1 protein has a direct effect on the viral ribonucleoprotein complex. In a minireplicon system, avian-like NP from swine virus isolates was more sensitive to inhibition by murine Mx1 than NP from human influenza A virus isolates. Likewise, murine Mx1 displaced avian NP from the viral ribonucleoprotein complex more easily than human NP. The stronger resistance of the A/H1N1 pandemic 2009 virus against Mx1 also correlated with reduced inhibition of the PB2-NP interaction. Our findings support a model in which Mx1 interacts with the influenza ribonucleoprotein complex and interferes with its assembly by disturbing the PB2-NP interaction.

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“…Primer extension assays were performed by using a primer extension system avian myeloblastosis virus (AMV) reverse transcriptase kit (Promega), as described previously (19). Five micrograms of total RNA was mixed with 0.5 pmol (each) of two DNA primers, labeled at the 5= end with [␥-…”

Section: Methodsmentioning

confidence: 99%

A Nucleolar Protein, Ribosomal RNA Processing 1 Homolog B (RRP1B), Enhances the Recruitment of Cellular mRNA in Influenza Virus Transcription

Hsu

Lee

et al. 2015

J Virol

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Influenza A virus (IAV) undergoes RNA transcription by a unique capped-mRNA-dependent transcription, which is carried out by the viral RNA-dependent RNA polymerase (RdRp), consisting of the viral PA, PB1, and PB2 proteins. However, how the viral RdRp utilizes cellular factors for virus transcription is not clear. Previously, we conducted a genome-wide pooled short hairpin RNA (shRNA) screen to identify host factors important for influenza A virus replication. Ribosomal RNA processing 1 homolog B (RRP1B) was identified as one of the candidates. RRP1B is a nucleolar protein involved in ribosomal biogenesis. Upon IAV infection, part of RRP1B was translocated from the nucleolus to the nucleoplasm, where viral RNA synthesis likely takes place. The depletion of RRP1B significantly reduced IAV mRNA transcription in a minireplicon assay and in virus-infected cells. Furthermore, we showed that RRP1B interacted with PB1 and PB2 of the RdRp and formed a coimmunoprecipitable complex with RdRp. The depletion of RRP1B reduced the amount of capped mRNA in the RdRp complex. Taken together, these findings indicate that RRP1B is a host factor essential for IAV transcription and provide a target for new antivirals. IMPORTANCEInfluenza virus is an important human pathogen that causes significant morbidity and mortality and threatens the human population with epidemics and pandemics every year. Due to the high mutation rate of the virus, antiviral drugs targeting viral proteins might ultimately lose their effectiveness. An alternative strategy that explores the genetic stability of host factors indispensable for influenza virus replication would thus be desirable. Here, we characterized the rRNA processing 1 homolog B (RRP1B) protein as an important cellular factor for influenza A virus transcription. We showed that silencing RRP1B hampered viral RNA-dependent RNA polymerase (RdRp) activity, which is responsible for virus transcription and replication. Furthermore, we reported that RRP1B is crucial for RdRp binding to cellular capped mRNA, which is a critical step of virus transcription. Our study not only provides a deeper understanding of influenza virus-host interplay, but also suggests a potential target for antiviral drug development.

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Ubiquitination and deubiquitination of NP protein regulates influenza A virus RNA replication

Cited by 111 publications

References 50 publications

Mx Proteins: Antiviral Gatekeepers That Restrain the Uninvited

Mx Proteins: Antiviral Gatekeepers That Restrain the Uninvited

Interferon-Inducible Protein Mx1 Inhibits Influenza Virus by Interfering with Functional Viral Ribonucleoprotein Complex Assembly

A Nucleolar Protein, Ribosomal RNA Processing 1 Homolog B (RRP1B), Enhances the Recruitment of Cellular mRNA in Influenza Virus Transcription

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