Constitutive expression of (2′–5′) oligo A synthetase confers resistance to picornavirus infection

Chebath, Judith; Benech, Philippe; Revel, M; Vigneron, Marc

doi:10.1038/330587a0

Cited by 264 publications

(146 citation statements)

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“…The role played by RNase L in IFN-induced antiviral activity has clearly been demonstrated by transfection of 2-5A or stabilized 2-5A analogues in intact cells [49][50][51][52][53][54]. The cloning of 2-5A-synthetase [55,56] and RNase L [1] allowed the definitive demonstration of the antiviral activity of RNase L. The constitutive expression of the 40 kDa 2-5A-synthetase confers resistance to EMCV and mengovirus [57,58] and over expression of the 69 kDa form of 2-5A-synthetase protein in human cells inhibits the replication of EMCV [59]. Similarly, the antiviral activity of IFN against EMCV was inhibited by the expression of a dominant negative mutant of RNase L [28] or treatment with a 2-5A antagonist [49,53,54].…”

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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“…The effect was reversible by a specific neutralizing monoclonal antibody to IL-8. Moreover, IL-8 could increase EMCV viral RNA synthesis and infectious virus yield, accompanied with a decrease in 2',5'-oligoadenylate synthetase (OAS) activity, which can be upregulated by IFN [29]. Hence, we examined the effects of IL-8 on the antiviral activities of IFN-␣.…”

Section: Reduction Of Ifn Antiviral Activities By Il-8mentioning

confidence: 99%

Potential involvement of IL-8 in the pathogenesis of human cytomegalovirus infection

Murayama

Mukaida

Khabar

et al. 1998

Journal of Leukocyte Biology

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“…2-5A-antisense chimeras contain 2-5A covalently attached through butanediol phosphate linkers to antisense oligonucleotide. In nature, RNase L functions as a component of the 2-5A system (14), implicated in the antiviral activity of interferon against picornaviruses (15)(16)(17)(18)(19), vaccinia virus (20,21), and reovirus (22). In the 2-5A-antisense approach, RNase L is converted to a highly specific endoribonuclease capable of selectively cleaving individual RNA targets.…”

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Targeting RNA decay with 2′,5′ oligoadenylate-antisense in respiratory syncytial virus-infected cells

Cirino

Xiao

et al. 1997

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

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Treatment of human cells with 2 ,5 oligoadenylate covalently linked to antisense (2-5A-antisense) results in the selective cleavage of targeted RNA species by 2-5A-dependent RNase L. Here we show that 2-5A-antisense containing stabilizing modifications at both termini are effective in suppressing the replication of respiratory syncytial virus (RSV) in human tracheal epithelial cells. The affinity of 2-5A-antisense for different regions in the RSV M2 and L mRNAs was predicted from a computer-generated model of the RNA secondary structure. The most potent 2-5A-antisense molecule caused a highly effective, dose-dependent suppression of RSV yields when added to previously infected cells. In contrast, control oligonucleotides, including an inactive dimeric form of 2-5A linked to antisense, 2-5A linked to a randomized sequence of nucleotides, and antisense molecules lacking 2-5A, had minimal effects on virus replication. The specificity of this approach was shown by reverse transcriptase-coupled PCR analysis of RSV M2, P, and N mRNA and of cellular glyceraldehyde-3-phosphate dehydrogenase mRNA. The RSV M2 mRNA amounts were depleted after treating RSV-infected cells with 2-5A-antisense targeted to this mRNA, whereas the amounts of the other RNA species were unchanged. These studies demonstrate that 2 ,5 oligoadenylate covalently linked to antisense (2-5A-antisense) can effectively suppress RSV replication by directing the cellular RNase L to selectively degrade an essential viral mRNA.Respiratory syncytial virus (RSV), a nonsegmented, negativestrand RNA virus in the pneumovirus genus of Paramyxoviridae, is a major cause of lower respiratory disease, resulting in 90,000 hospitalizations and 4500 deaths per year in infants and young children in the United States (1). Of growing concern are outbreaks of RSV within institutionalized elderly (2) and immunodeficient (1) adults. There is only one approved anti-RSV compound, ribavirin, which reduces virus shedding in infected children, but has no effect on mortality or duration of hospitalization (3). In the search for alternative antiviral strategies, we have investigated the potential of novel chimeric antisense molecules, 2-5A-antisense, in the control of RSV infections.Zamecnik and Stephenson were the first to report an antiviral effect of antisense oligonucleotides by showing that replication of the retrovirus Rous sarcoma virus could be inhibited by the addition of oligonucleotides complementary in sequence to reiterated terminal sequences of the viral 35S RNA (4). Subsequently, antisense oligonucleotides have been used against a wide range of different types of viruses, including the negative-strand RNA viruses such as rabies virus (5) and influenza virus (6), positive-strand RNA viruses such as dengue virus (7), DNA viruses including hepatitis B (8) and herpes simplex virus type 1 (9), and the retrovirus HIV-1 (10, 11). Despite encouraging results, significant challenges remain in the development of antisense oligonucleotides as antiviral agents. For instance, ...

show abstract

Constitutive expression of (2′–5′) oligo A synthetase confers resistance to picornavirus infection

Cited by 264 publications

References 1 publication

Diverse functions of RNase L and implications in pathology

Diverse functions of RNase L and implications in pathology

Potential involvement of IL-8 in the pathogenesis of human cytomegalovirus infection

Targeting RNA decay with 2′,5′ oligoadenylate-antisense in respiratory syncytial virus-infected cells

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