The primary function of RNA binding by the influenza A virus NS1 protein in infected cells: Inhibiting the 2′-5′ oligo (A) synthetase/RNase L pathway

Min, Ji-Young; Krug, Robert M.

doi:10.1073/pnas.0602184103

Cited by 416 publications

(376 citation statements)

References 37 publications

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“…Inhibition of 2-5A synthetase during vaccinia virus infection is mediated by the E3L, viral encoded dsRNA binding proteins [81][82][83]. During influenza A virus infection, the viral protein NS1A sequesters dsRNA and inhibits 2-5A-synthetase activation [84]. Some viruses recruit a host protein to inhibit RNase L activity.…”

Section: Iii) Biological Activities Of Rnase L 1) Antiviral Activitymentioning

confidence: 99%

Diverse functions of RNase L and implications in pathology

Bisbal

Silverman

2007

Biochimie

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The endoribonuclease L (RNase L) is the effector of the 2-5A system, a major enzymatic pathway involved in the molecular mechanism of interferons (IFN). RNase L is a very unusual nuclease with a complex mechanism of regulation. It is a latent enzyme, expressed in nearly every mammalian cell type. Its activation requires its binding to a small oligonucleotide, 2-5A. 2-5A is a series of unique 5′-triphosphorylated oligoadenylates with 2′-5′ phosphodiester bonds. By regulating viral and cellular RNA expression, RNase L plays an important role in the antiviral and antiproliferative activities of IFN and contributes to innate immunity and cell metabolism. The 2-5A/RNase L pathway is implicated in mediating apoptosis in response to viral infections and to several types of external stimuli. Several recent studies have suggested that RNase L could have a role in cancer biology and evidence of a tumor suppressor function of RNase L has emerged from studies on the genetics of hereditary prostate cancer. KeywordsInterferon; RNase L; RNA expression; apoptosis; prostate; virus; cancer I) IntroductionThe endoribonuclease L (RNase L) is the effector of the 2-5A system, a major enzymatic pathway regulated by interferons (IFN) [1] (Figure 1). The 2-5A system is one of the two antiviral pathways induced by IFN and activated by double stranded RNA (dsRNA), the other is mediated by the dsRNA dependent protein kinase (PKR) [2]. RNase L is a very unusual nuclease. It is a latent enzyme, expressed in nearly every mammalian cell type. Its activation requires its binding to a small oligonucleotide, 2-5A ( Figure 1). 2-5A itself is very unusual, consisting of a series of 5′-triphosphorylated oligoadenylates with 2′-5′ phosphodiester bonds in contrast to the 3′-5′ linkages found in RNA and DNA. The initial and essential observation was made by Ian Kerr's group in 1974 reporting an IFN-induced increase in the sensitivity of protein synthesis to inhibition by dsRNA [3]. Peter Lengyel's group observed increased nuclease activity in extracts of interferon treated cells incubated with dsRNA [4,5]. The identification by Ian Kerr's group of the activators of this nuclease, 2-5A [6] and of the enzyme responsible for their synthesis, the 2-5A-synthetase [7][8][9], led to the discovery of the 2-5A pathway. Clemens and Williams directly demonstrated a nuclease, now recognized as RNase Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. (Figure 2). The N-terminal domain could be considered as the regulatory domain of RNase L. It is composed of eight complete and one partial ankyrin motifs (R1-R9). Two wal...

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Section: Iii) Biological Activities Of Rnase L 1) Antiviral Activitymentioning

confidence: 99%

Diverse functions of RNase L and implications in pathology

Bisbal

Silverman

2007

Biochimie

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“…To perform such activities, NS1 functionally interacts with virus-and͞or cell-derived factors: e.g., NS1 blocks the activation of two IFN-inducible antiviral proteins: 2Ј-5Ј-oligoadenylate synthetase (2Ј-5Ј-OAS), and the dsRNA-dependent protein kinase R (PKR). In infected cells, the binding of NS1 to dsRNA (a putative by-product of viral RNA genome replication) has been implicated in the inhibition of cellular 2Ј-5Ј-OAS (6). dsRNA-binding by NS1 may also be a requirement for blocking the activation of PKR in vitro (7), but studies now suggest that this inhibition, both in vitro and in vivo, may occur via direct interaction of NS1 with PKR (8,9).…”

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confidence: 99%

Influenza A virus NS1 protein binds p85β and activates phosphatidylinositol-3-kinase signaling

Hale

Jackson

Chen

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

263

331

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Influenza A virus NS1 is a multifunctional protein, and in virusinfected cells NS1 modulates a number of host-cell processes by interacting with cellular factors. Here, we report that NS1 binds directly to p85␤, a regulatory subunit of phosphatidylinositol-3-kinase (PI3K), but not to the related p85␣ subunit. Activation of PI3K in influenza virus-infected cells depended on genome replication, and showed kinetics that correlated with NS1 expression. Additionally, it was found that expression of NS1 alone was sufficient to constitutively activate PI3K, causing the phosphorylation of a downstream mediator of PI3K signal transduction, Akt. Mutational analysis of a potential SH2-binding motif within NS1 indicated that the highly conserved tyrosine at residue 89 is important for both the interaction with p85␤, and the activation of PI3K. A mutant influenza virus (A͞Udorn͞72) expressing NS1 with the Y89F amino acid substitution exhibited a small-plaque phenotype, and grew more slowly in tissue culture than WT virus. These data suggest that activation of PI3K signaling in influenza A virus-infected cells is important for efficient virus replication.Akt phosphorylation ͉ multifunctional NS1 protein ͉ reverse genetics

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“…An important viral factor is the multifunctional NS1 protein, which is able to modulate several antiviral pathways. For example, NS1 blocks 29-59-oligoadenylate synthetase-mediated activation of RNase L (Min & Krug, 2006) and limits the induction of IFN-b (Wang et al, 2000;Ludwig et al, 2002). Furthermore, NS1 binds to and inhibits the cytoplasmic dsRNA sensor retinoic acidinducible gene product I (Guo et al, 2007;Mibayashi et al, 2007) and blocks protein kinase R-mediated inhibition of protein synthesis (Bergmann et al, 2000;Min et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Differential RNA silencing suppression activity of NS1 proteins from different influenza A virus strains

Vries

Haasnoot

Fouchier³

et al. 2009

Journal of General Virology

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The NS1 gene of influenza A virus encodes a multi-functional protein that plays an important role in counteracting cellular antiviral mechanisms such as the interferon (IFN), protein kinase R and retinoic acid-inducible gene product I pathways. In addition, NS1 has recently been shown to have RNA interference (RNAi) or RNA silencing suppression (RSS) activity. This study analysed the IFN antagonistic activity of NS1 and the RSS activity for several influenza subtypes: H1N1, H3N2, H5N1 and H7N7. It was shown that the various NS1 proteins were capable of inhibiting the activation of an IFN-responsive promoter. However, differential RSS activity was measured among the NS1 variants. The NS1 protein of strain A/WSN/33 (H1N1) was most potent in suppressing short hairpin RNA-mediated gene silencing. In contrast, NS1 proteins of the highly pathogenic H5N1 strains A/VN/1194/04 and A/HK/156/97 were most potent in complementing the RSS function of the human immunodeficiency virus type 1 Tat protein. These results show that the ability of NS1 to suppress RNAi varies among influenza strains and is likely to contribute to differences in viral replication capacity and pathogenicity.

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The primary function of RNA binding by the influenza A virus NS1 protein in infected cells: Inhibiting the 2′-5′ oligo (A) synthetase/RNase L pathway

Cited by 416 publications

References 37 publications

Diverse functions of RNase L and implications in pathology

Diverse functions of RNase L and implications in pathology

Influenza A virus NS1 protein binds p85β and activates phosphatidylinositol-3-kinase signaling

Differential RNA silencing suppression activity of NS1 proteins from different influenza A virus strains

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