Interaction of Polymerase Subunit PB2 and NP with Importin α1 Is a Determinant of Host Range of Influenza A Virus

Gabriel, Gülşah; Herwig, Astrid; Klenk, Hans Dieter

doi:10.1371/journal.ppat.0040011

Cited by 338 publications

(384 citation statements)

References 37 publications

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“…[11][12][13][14][15] Here we summarise new structural, biochemical and genetic evidences that have set the stage for a more profound understanding of influenza virus transcription and replication, and discuss alternative models to describe the mechanisms of these processes (reviewed in ref. [16][17][18].…”

Section: O N O T D I S T R I B U T Ementioning

confidence: 99%

“…80 In addition, mutation analyses of the PB2 NLS indicated that the transport of PB2 to the nucleus and the formation of a functional polymerase complex are closely correlated events 14 and represent host-regulated steps in the virus multiplication cycle. 13 On the other hand, the polymerase complex may play a role during virus mRNA translation. Although early in vitro studies indicated that the polymerase complex dissociates from the cap-structure soon after cap-snatching, 81 no in vivo studies have 62 the polymerase complex present in the recombinant RNP (middle, yellow), 34 and a polymerase-vRNA complex (bottom, blue).…”

Section: To Switch or Not To Switchmentioning

confidence: 99%

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The influenza virus RNA synthesis machine

et al. 2011

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Section: O N O T D I S T R I B U T Ementioning

confidence: 99%

Section: To Switch or Not To Switchmentioning

confidence: 99%

The influenza virus RNA synthesis machine

et al. 2011

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“…The major hypothesis that has been extensively investigated is that residue 627 interacts with essential host factors or small molecules that differ between mammalian and avian species (8,14). Over the last few years, a number of proteins have been proposed as potential candidate host factors, although none have been specifically found to be associated with the 627 position (15,16). Another study reported that PB2 K627E binds influenza nucleoprotein (NP) in human cells when expressed alone, but not when assembled into the trimeric polymerase complex, suggesting that this mutation might induce species-specific conformational alterations that disrupt ribonucleoprotein assembly (17).…”

mentioning

confidence: 99%

Biochemical Impact of the Host Adaptation-associated PB2 E627K Mutation on the Temperature-dependent RNA Synthesis Kinetics of Influenza A Virus Polymerase Complex

Aggarwal

Dewhurst

Takimoto

et al. 2011

Journal of Biological Chemistry

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Most avian influenza A viruses, which preferentially replicate at the high temperatures found in the digestive tract of birds, have a glutamic acid at residue 627 of the viral RNA polymerase PB2 subunit (Glu-627), whereas the human viruses, which optimally replicate at the low temperatures observed in the human respiratory tract, have a lysine (Lys-627). The mechanism of action for this mutation is still not understood, although interaction with host factors has been proposed to play a major role. In this study, we explored an alternative, yet related, hypothesis that this PB2 mutation may alter the temperature-dependent enzymatic polymerase activity of the viral polymerase. First, the avian polymerase protein, which was purified from baculovirus expression system, indeed remained significantly active at higher temperatures (i.e. 37 and 42°C), whereas the human E627K mutant drastically lost activity at these high temperatures. Second, our steady-state kinetics data revealed that the human E627K mutant polymerase is catalytically more active than the avian Glu-627 polymerase at 34°C. Importantly, the E627K mutation elevates apparent K cat at low temperatures with little effect on K m , suggesting that the E627K mutation alters the biochemical steps involved in enzyme catalysis rather than the interaction with the incoming NTP. Third, this temperature-dependent kinetic impact of the human E627K mutation was also observed with different RNA templates, with different primers and also in the presence of nucleoprotein. In conclusion, our study suggests that the amino acid sequence variations at residue 627 of PB2 subunit can directly alter the enzyme kinetics of influenza polymerase.

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“…Additionally, several other mutations in PA, PB1, and PB2 were also shown to influence the polymerase activity [5][6][7][8][9][10][11][12]. Furthermore, the interaction of NP and PB2 with Importin α1 was found to be a determinant of host range as well [13].…”

Section: Introductionmentioning

confidence: 95%

Correlated mutations in the four influenza proteins essential for viral RNA synthesis, host adaptation, and virulence: NP, PA, PB1, and PB2

Hu¹

2010

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The NP, PA, PB1, and PB2 proteins of influenza viruses together are responsible for the transcription and replication of viral RNA, and the latter three proteins comprise the viral polymerase. Two recent reports indicated that the mutation at site 627 of PB2 plays a key role in host range and increased virulence of influenza viruses, and could be compensated by multiple mutations at other sites of PB2, suggesting the association of this mutation with those at other sites. The objective of this study was to analyze the co-mutated sites within and between these important proteins of influenza. With mutual information, a set of statistically significant comutated position pairs (P value = 0) in NP, PA, PB1, and PB2 of avian, human, pandemic 2009 H1N1, and swine influenza were identified, based on which several highly connected networks of correlated sites in NP, PA, PB1, and PB2 were discovered. These correlation networks further illustrated the inner functional dependence of the four proteins that are critical for host adaptation and pathogenicity. Mutual information was also applied to quantify the correlation of sites within each individual protein and between proteins. In general, the inter protein correlation of the four proteins was stronger than the intra protein correlation. Finally, the correlation patterns of the four proteins of pandemic 2009 H1N1 were found to be closer to those of avian and human than to swine influenza, thus rendering a novel insight into the interaction of the four proteins of the pandemic 2009 H1N1 virus when compared to avian, human, and swine influenza and how the origin of these four proteins might affect the correlation patterns uncovered in this analysis.

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Interaction of Polymerase Subunit PB2 and NP with Importin α1 Is a Determinant of Host Range of Influenza A Virus

Cited by 338 publications

References 37 publications

The influenza virus RNA synthesis machine

The influenza virus RNA synthesis machine

Biochemical Impact of the Host Adaptation-associated PB2 E627K Mutation on the Temperature-dependent RNA Synthesis Kinetics of Influenza A Virus Polymerase Complex

Correlated mutations in the four influenza proteins essential for viral RNA synthesis, host adaptation, and virulence: NP, PA, PB1, and PB2

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