Identification of Novel Influenza A Virus Proteins Translated from PA mRNA

Muramoto, Yukiko; Noda, Takeshi; Kawakami, Eiryo; Akkina, Ramesh; Kawaoka, Yoshihiro

doi:10.1128/jvi.02656-12

Cited by 198 publications

(171 citation statements)

References 37 publications

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“…Among the alternative viral proteins, M2, M42, NS2, and NS3 are translated from spliced mRNA (5-16), PB1-F2, PB1-N40, PA-N155, and PA-N182 are expressed via an alternative translation initiation process (17)(18)(19)(20)(21), and PA-X is expressed via a ribosomal frameshift (25). PB2-S1 is the second viral protein expressed from the PB2 segment and is the fifth viral protein translated from a spliced mRNA.…”

Section: Discussionmentioning

confidence: 99%

“…Approximately 30 of Ͼ18,000 isolates likely express M42 and NS3, based on nucleotide sequence analyses (15,16). PB1-F2, PB1-N40, PA-N155, and PA-N182 are expressed from alternative translation initiation sites in the PB1 and PA segments (17)(18)(19)(20)(21). Although the functions of PB1-N40, PA-N155, and PA-N182 remain unclear, PB1-F2 is associated with pathogenicity, inducing apoptosis and a reduction in the mitochondrial inner membrane potential (17,22).…”

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confidence: 99%

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Identification of a Novel Viral Protein Expressed from the PB2 Segment of Influenza A Virus

Yamayoshi

Watanabe

Goto

et al. 2016

J Virol

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Over the past 2 decades, several novel influenza virus proteins have been identified that modulate viral infections in vitro and/or in vivo. The PB2 segment, which is one of the longest influenza A virus segments, is known to encode only one viral protein, PB2. In the present study, we used reverse transcription-PCR (RT-PCR) targeting viral mRNAs transcribed from the PB2 segment to look for novel viral proteins encoded by spliced mRNAs. We identified a new viral protein, PB2-S1, encoded by a novel spliced mRNA in which the region corresponding to nucleotides 1513 to 1894 of the PB2 mRNA is deleted. PB2-S1 was detected in virusinfected cells and in cells transfected with a protein expression plasmid encoding PB2. PB2-S1 localized to mitochondria, inhibited the RIG-I-dependent interferon signaling pathway, and interfered with viral polymerase activity (dependent on its PB1-binding capability). The nucleotide sequences around the splicing donor and acceptor sites for PB2-S1 were highly conserved among pre-2009 human H1N1 viruses but not among human H1N1pdm and H3N2 viruses. PB2-S1-deficient viruses, however, showed growth kinetics in MDCK cells and virulence in mice similar to those of wild-type virus. The biological significance of PB2-S1 to the replication and pathogenicity of seasonal H1N1 influenza A viruses warrants further investigation. IMPORTANCE Transcriptome analysis of cells infected with influenza

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Identification of a Novel Viral Protein Expressed from the PB2 Segment of Influenza A Virus

Yamayoshi

Watanabe

Goto

et al. 2016

J Virol

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“…The genome consists of eight segmented RNA molecules of negative polarity. The majority of influenza A virus strains encode 12-14 viral proteins (Muramoto et al, 2012). Of those, NP and RNA polymerase subunits PB2, PB1 and PA are associated with the RNA genome, forming a viral nucleoprotein (vRNP) complex.…”

Section: Introductionmentioning

confidence: 99%

The role of Ran-binding protein 3 during influenza A virus replication

Predicala

Zhou

2013

Journal of General Virology

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Influenza A virus vRNP nuclear export is CRM1-dependent. Ran-binding protein 3 (RanBP3) is a Ran-interacting protein that is best known for its role as a cofactor of CRM1-mediated cargo nuclear export. In this study, we investigated the role of RanBP3 during the influenza A virus life cycle. We found that RanBP3 was phosphorylated at Ser58 in the early and late phases of infection. Knockdown of RanBP3 expression led to vRNP nuclear retention, suggesting that RanBP3 is involved in vRNP nuclear export. Moreover, we demonstrated that the function of RanBP3 during vRNP nuclear export is regulated by phosphorylation at Ser58, and that RanBP3 phosphorylation is modulated by both PI3K/Akt and Ras/ERK/RSK pathways in the late phase of viral infection.

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“…IAV belongs to the Orthomyxoviridae family, and its genome consists of eight negative-sense RNA segments encoding up to 17 viral proteins (4)(5)(6)(7)(8)(9). The viral RNA (vRNA) exists as a form of viral ribonucleoprotein complexes (vRNPs) containing vRNA, nucleoprotein (NP), and three viral polymerase proteins (PB1, PB2, and PA).…”

mentioning

confidence: 99%

Interaction of NS2 with AIMP2 Facilitates the Switch from Ubiquitination to SUMOylation of M1 in Influenza A Virus-Infected Cells

Gao

Liu

et al. 2015

J Virol

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Influenza A viruses (IAVs) rely on host factors to support their life cycle, as viral proteins hijack or interact with cellular proteins to execute their functions. Identification and understanding of these factors would increase our knowledge of the molecular mechanisms manipulated by the viruses. In this study, we searched for novel binding partners of the influenza A virus NS2 protein, the nuclear export protein responsible for overcoming host range restriction, by a yeast two-hybrid screening assay and glutathione S-transferase-pulldown and coimmunoprecipitation assays and identified AIMP2, a potent tumor suppressor that usually functions to regulate protein stability, as one of the major NS2-binding candidates. We found that the presence of NS2 protected AIMP2 from ubiquitin-mediated degradation in NS2-transfected cells and AIMP2 functioned as a positive regulator of IAV replication. Interestingly, AIMP2 had no significant effect on NS2 but enhanced the stability of the matrix protein M1. Further, we provide evidence that AIMP2 recruitment switches the modification of M1 from ubiquitination to SUMOylation, which occurs on the same attachment site (K242) on M1 and thereby promotes M1-mediated viral ribonucleoprotein complex nuclear export to increase viral replication. Collectively, our results reveal a new mechanism of AIMP2 mediation of influenza virus replication. IMPORTANCEAlthough the ubiquitination of M1 during IAV infection has been observed, the precise modification site and the molecular consequences of this modification remain obscure. Here, we demonstrate for the first time that ubiquitin and SUMO compete for the same lysine (K242) on M1 and the interaction of NS2 with AIMP2 facilitates the switch of the M1 modification from ubiquitination to SUMOylation, thus increasing viral replication. Influenza A virus (IAV) is a significant cause of morbidity and mortality in both humans and animal species owing to its ability to cause yearly epidemics and occasional pandemics (1-3). Like other viruses, IAV hijacks the host cellular machinery to support its life cycle. Thus, identification and characterization of the interactions between viral components and specific host factors would help provide an understanding of the mechanisms by which the viruses acquire human pandemic potential.IAV belongs to the Orthomyxoviridae family, and its genome consists of eight negative-sense RNA segments encoding up to 17 viral proteins (4-9). The viral RNA (vRNA) exists as a form of viral ribonucleoprotein complexes (vRNPs) containing vRNA, nucleoprotein (NP), and three viral polymerase proteins (PB1, PB2, and PA). Unlike most other RNA viruses, influenza virus transcribes and replicates its genome in the nucleus. Thus, after it enters a host cell, vRNPs enter the nucleus to complete transcription and replication (10). The newly synthesized vRNPs are exported from the nucleus for packaging into progeny virions (11). In this regard, efficient nuclear export of vRNPs is essential for productive infection.NS2, also kn...

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Identification of Novel Influenza A Virus Proteins Translated from PA mRNA

Cited by 198 publications

References 37 publications

Identification of a Novel Viral Protein Expressed from the PB2 Segment of Influenza A Virus

Identification of a Novel Viral Protein Expressed from the PB2 Segment of Influenza A Virus

The role of Ran-binding protein 3 during influenza A virus replication

Interaction of NS2 with AIMP2 Facilitates the Switch from Ubiquitination to SUMOylation of M1 in Influenza A Virus-Infected Cells

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