Overlapping signals for translational regulation and packaging of influenza A virus segment 2

Wise, Helen; Barbezange, Cyril; Jagger, Brett W.; Dalton, Rosa M.; Curran, Martin D.; Taubenberger, Jeffery K.; Anderson, Emma; Digard, Paul

doi:10.1093/nar/gkr487

Cited by 64 publications

(61 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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).…”

mentioning

confidence: 99%

See 1 more Smart Citation

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

Yamayoshi

Watanabe

Goto

et al. 2016

J Virol

View full text Add to dashboard Cite

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

show abstract

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

View full text Add to dashboard Cite

show abstract

“…Using chimeric PB1 genes we show that the coselection of Udorn NA and PB1 gene segments is dependent on interactions involving the central coding sequence of PB1 rather than the previously defined packaging sequences (9)(10)(11)(12).…”

mentioning

confidence: 93%

Influenza Virus PB1 and Neuraminidase Gene Segments Can Cosegregate during Vaccine Reassortment Driven by Interactions in the PB1 Coding Region

Cobbin

Ong

Verity

et al. 2014

J Virol

View full text Add to dashboard Cite

Egg-grown influenza vaccine yields are maximized by infection with a seed virus produced by "classical reassortment" of a seasonal isolate with a highly egg-adapted strain. Seed viruses are selected based on a high-growth phenotype and the presence of the seasonal hemagglutinin (HA) and neuraminidase (NA) surface antigens. Retrospective analysis of H3N2 vaccine seed viruses indicated that, unlike other internal proteins that were predominantly derived from the high-growth parent A/Puerto Rico/8/34 (PR8), the polymerase subunit PB1 could be derived from either parent depending on the seasonal strain. We have recently shown that A/Udorn/307/72 (Udorn) models a seasonal isolate that yields reassortants bearing the seasonal PB1 gene. This is despite the fact that the reverse genetics-derived virus that includes Udorn PB1 with Udorn HA and NA on a PR8 background has inferior growth compared to the corresponding virus with PR8 PB1. Here we use competitive plasmid transfections to investigate the mechanisms driving selection of a less fit virus and show that the Udorn PB1 gene segment cosegregates with the Udorn NA gene segment. Analysis of chimeric PB1 genes revealed that the coselection of NA and PB1 segments was not directed through the previously identified packaging sequences but through interactions involving the internal coding region of the PB1 gene. This study identifies associations between viral genes that can direct selection in classical reassortment for vaccine production and which may also be of relevance to the gene constellations observed in past antigenic shift events where creation of a pandemic virus has involved reassortment. IMPORTANCEInfluenza vaccine must be produced and administered in a timely manner in order to provide protection during the winter season, and poor-growing vaccine seed viruses can compromise this process. To maximize vaccine yields, manufacturers create hybrid influenza viruses with gene segments encoding the surface antigens from a seasonal virus isolate, important for immunity, and others from a virus with high growth properties. This involves coinfection of cells with both parent viruses and selection of dominant progeny bearing the seasonal antigens. We show that this method of creating hybrid viruses does not necessarily select for the best yielding virus because preferential pairing of gene segments when progeny viruses are produced determines the genetic makeup of the hybrids. This not only has implications for how hybrid viruses are selected for vaccine production but also sheds light on what drives and limits hybrid gene combinations that arise in nature, leading to pandemics.

show abstract

“…Since it has been proposed that the suboptimal Kozak consensus of PB1, with the unique 'U' nucleotide in the -3 position, is involved in regulating the expression of PB1-F2 protein by leaky ribosomal scanning (Chen et al, 2001;Kozak, 1991;Wise et al, 2011), the U-to-A mutation at the 23 position might be expected to result in defective expression of PB1-F2 protein. In order to examine whether the attenuation of WSN-PB1(23A) was caused by defective expression of PB1-F2, we made three mutations (T120C, C153G and G291A) (Ma et al, 2013;Su et al, 2012) in the coding region of both the wild-type and the Uto-A mutant virus to completely eliminate PB1-F2 expression in both viruses ( PB2 (1533) PB2 (19) PB1 (1711) PB1 (18) PA (1715) PA (17) H3 (430) H3 (6) NP (1737) NP (16) N2 (902) N2 (6) M (2619) M (14) NS (2202) PB1 (1711) NS (17) PB2 (2167) PB2 (18) PB1 (1872) PB1 (17) PA (2166) PA (17) H3 (703) H3 (5) NP (2140) NP (16) N2 (1023) N2 (6) M (2890) M (14) NS (2853) NS (17) PA (1715) H3 (430) NP (1737) N2 (902) M (2619) NS ( PB2 (2167) PB1 (1872) PA (2166) H3 …”

Section: Segment-specific Ncrs Mediate the Synthesis Of Viral Rnas Anmentioning

confidence: 99%

Influenza A virus utilizes a suboptimal Kozak sequence to fine-tune virus replication and host response

Wang

Peng

Zhao

et al. 2015

Journal of General Virology

View full text Add to dashboard Cite

The segment-specific non-coding regions (NCRs) of influenza A virus RNA genome play important roles in controlling viral RNA transcription, replication and genome packaging. In this report, we present, for the first time to our knowledge, a full view of the segment-specific NCRs of all influenza A viruses by bioinformatics analysis. Our systematic functional analysis revealed that the eight segment-specific NCRs identified could differentially regulate viral RNA synthesis and protein expression at both transcription and translation levels. Interestingly, a highly conserved suboptimal nucleotide at "3 position of the Kozak sequence, which downregulated protein expression at the translation level, was only present in the segment-specific NCR of PB1. By reverse genetics, we demonstrate that recombinant viruses with an optimized Kozak sequence at the "3 position in PB1 resulted in a significant multiple-cycle replication reduction that was independent of PB1-F2 expression. Our detailed dynamic analysis of virus infection revealed that the mutant virus displays slightly altered dynamics from the wild-type virus on both viral RNA synthesis and protein production. Furthermore, we demonstrated that the level of PB1 expression is involved in regulating type I IFN production. Together, these data reveal a novel strategy exploited by influenza A virus to fine-tune virus replication dynamics and host antiviral response through regulating PB1 protein expression.

show abstract

Overlapping signals for translational regulation and packaging of influenza A virus segment 2

Cited by 64 publications

References 58 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

Influenza Virus PB1 and Neuraminidase Gene Segments Can Cosegregate during Vaccine Reassortment Driven by Interactions in the PB1 Coding Region

Influenza A virus utilizes a suboptimal Kozak sequence to fine-tune virus replication and host response

Contact Info

Product

Resources

About