Phosphorylation of Influenza Virus Nucleoprotein in vivo

Petri, Thomas; Dimmock, Nigel J.

doi:10.1099/0022-1317-57-1-185

Cited by 30 publications

(18 citation statements)

References 14 publications

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“…In addition, bright cytoplasmic foci of NS1 were detected in the cytoplasm of ESEV-infected duck cells at 4 h and 8 h p.i. These foci were reminiscent of previously described virus-induced cytoplasmic inclusions that remain of uncertain identity (34). Taken together, these results suggest that ESEV and RSKV do not differ in their abilities to infect human, mouse, and duck cells and that both viruses initiate replication with similar kinetics.…”

Section: Resultssupporting

confidence: 78%

Species-Specific Contribution of the Four C-Terminal Amino Acids of Influenza A Virus NS1 Protein to Virulence

Soubies

Volmer

Croville

et al. 2010

J Virol

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Large-scale sequence analyses of influenza viruses revealed that nonstructural 1 (NS1) proteins from avian influenza viruses have a conserved C-terminal ESEV amino acid motif, while NS1 proteins from typical human influenza viruses have a C-terminal RSKV motif. To test the influence of the C-terminal domains of NS1 on the virulence of an avian influenza virus, we generated a wild-type H7N1 virus with an ESEV motif and a mutant virus with an NS1 protein containing a C-terminal RSKV motif by reverse genetics. We compared the phenotypes of these viruses in vitro in human, mouse, and duck cells as well as in vivo in mice and ducks. In human cells, the human C-terminal RSKV domain increased virus replication. In contrast, the avian Cterminal ESEV motif of NS1 increased virulence in mice. We linked this increase in pathogenicity in mice to an increase in virus replication and to a more severe lung inflammation associated with a higher level of production of type I interferons. Interestingly, the human C-terminal RSKV motif of NS1 increased viral replication in ducks. H7N1 virus with a C-terminal RSKV motif replicated to higher levels in ducks and induced higher levels of Mx, a type I interferon-stimulated gene. Thus, we identify the C-terminal domain of NS1 as a species-specific virulence domain.

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Section: Resultssupporting

confidence: 78%

Species-Specific Contribution of the Four C-Terminal Amino Acids of Influenza A Virus NS1 Protein to Virulence

Soubies

Volmer

Croville

et al. 2010

J Virol

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“…Several viral protein components of influenza vRNPs are known to be phosphoproteins, including PA (47), NP (23,43), M1 (13,14,23), and NEP/NS2 (46), and hyperphosphorylation of a mutant M1 protein has been shown to cause its aberrant nuclear retention (57). Conflicting results concerning the relationship between NP phosphorylation and nuclear export have been reported: one study reported that phosphorylated NP accumulated in the nucleus and cytoplasm with similar kinetics (41), suggesting that phosphorylation did not affect NP nucleocytoplasmic trafficking, whereas another study found that vRNPs isolated from the nucleus contained much more phosphorylated NP than those from the cytoplasm, consistent with differential nuclear export (2). Whether phosphorylation of vRNP components regulates nuclear export and whether AG879 and A9 cause nuclear retention of vRNPs by specifically blocking that process require further investigation.…”

Section: Discussionmentioning

confidence: 99%

Receptor Tyrosine Kinase Inhibitors Block Multiple Steps of Influenza A Virus Replication

Kumar

Liang

Parslow

et al. 2011

J Virol

124

130

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Host signaling pathways play important roles in the replication of influenza virus, but their functional effects remain to be characterized at the molecular level. Here we identify two receptor tyrosine kinase inhibitors (RTKIs) of the tyrphostin class that exhibit robust antiviral activity against influenza A virus replication in cultured cells. One of these (AG879) is a selective inhibitor of the nerve growth factor receptor and human epidermal growth factor receptor 2 (TrkA/HER2) signaling; the other, tyrphostin A9 (A9), inhibits the plateletderived growth factor receptor (PDGFR) pathway. We find that each inhibits at least three postentry steps of the influenza virus life cycle: AG879 and A9 both strongly inhibit the synthesis of all three influenza virus RNA species, block Crm1-dependent nuclear export, and also prevent the release of viral particles through a pathway that is modulated by the lipid biosynthesis enzyme farnesyl diphosphate synthase (FPPS). Tests of short hairpin RNA (shRNA) knockdown and additional small-molecule inhibitors confirmed that interventions targeting TrkA can suppress influenza virus replication. Our study suggests that host cell receptor tyrosine kinase signaling is required for maximal influenza virus RNA synthesis, viral ribonucleoprotein (vRNP) nuclear export, and virus release and that specific RTKIs hold promise as novel anti-influenza virus therapeutics.

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“…However, in only a few cases has the significance of the phosphorylation been elucidated. With influenza A viruses three viral proteins have been found to be phosphorylated: the membrane (M) protein (Gregoriades et al, 1984), the non-structural protein NS 1 and the nucleoprotein (NP) (Privalsky & Penhoet, 1977, 1978Petri & Dimmock, 1981 ;Petri et al, 1982;Almond & Felsenreich, 1982;Kistner et al, 1985).…”

Section: Introductionmentioning

confidence: 99%

Differential Phosphorylation of the Nucleoprotein of Influenza A Viruses

Kistner

Müller

Scholtissek

1989

Journal of General Virology

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SUMMARYAn analysis of the nucleoprotein (NP) of 29 different influenza A viruses by phosphopeptide fingerprinting revealed three prototype patterns. The first, which was a complex pattern consisting of six to seven phosphopeptides, another which was relatively simple consisted of two or three phosphopeptides, and a third one which was complex but was missing the main phosphopeptide shared by the two other patterns. Phosphoserine was the only labelled phosphamino acid detected. A tentative deduction of two of the phosphate attachment sites (serine residues at positions 3 and 473) could be made by comparison of the known amino acid sequences of the NPs of 25 strains. No correlation was found between species specificity or subtype or year of isolation of the strains. During the infectious cycle the fingerprint underwent significant changes, indicating subtle phosphorylation and dephosphorylation of the NP at various stages during viral multiplication. Most of the phosphopeptides were metabolically stable; however one major phosphopeptide, which was not found in the NP of mature virions, exhibited a high turnover (presumably serine at position 3). The phosphopeptide fingerprint could be significantly influenced in vivo by the specific stimulation of cellular protein kinase C by the phorbol ester 12-O-tetradecanolyphorbol 13-acetate or by its inhibition with the isoquinoline sulphonamide H7.

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Phosphorylation of Influenza Virus Nucleoprotein in vivo

Cited by 30 publications

References 14 publications

Species-Specific Contribution of the Four C-Terminal Amino Acids of Influenza A Virus NS1 Protein to Virulence

Species-Specific Contribution of the Four C-Terminal Amino Acids of Influenza A Virus NS1 Protein to Virulence

Receptor Tyrosine Kinase Inhibitors Block Multiple Steps of Influenza A Virus Replication

Differential Phosphorylation of the Nucleoprotein of Influenza A Viruses

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