pppA2'p5'A2'p5'A: an inhibitor of protein synthesis synthesized with an enzyme fraction from interferon-treated cells.

Kerr, Ian M.; Brown, Ronald E.

doi:10.1073/pnas.75.1.256

Cited by 725 publications

(256 citation statements)

References 17 publications

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“…By that time, members of the Kerr lab (notably Ara Hovanessian and Bryan Williams with collaborator Michael Clemens) had firmly laid the groundwork by discovering 2-5A synthetase (OAS) activity [32], elucidating the chemical structure of 2-5A [9], and demonstrating that isolated and purified 2-5A activated the 2-5A dependent RNase [33](now referred to as "RNase L"; the "L" stands for "latent"). Complementary work in the labs of Peter Lengyel, Michel Revel, Corrado Baglioni and Charles Samuel gave impetus to these early studies [34][35][36][37].…”

Section: Monitoring the Presence And Activation Of Rnase L In Intact mentioning

confidence: 99%

“…Complementary work in the labs of Peter Lengyel, Michel Revel, Corrado Baglioni and Charles Samuel gave impetus to these early studies [34][35][36][37]. I came to the Kerr lab because of my interest in unusual nucleotide regulators and my fascination with Ian Kerr's remarkable discovery of 2-5A [9,38]. The discovery of 2-5A followed Ian Kerr's observation of an IFN-induced increase in the sensitivity of protein synthesis to inhibition by dsRNA [39][40][41].…”

Section: Monitoring the Presence And Activation Of Rnase L In Intact mentioning

confidence: 99%

“…In mice, in addition to OAS2 and OAS3 there are 7 separate OAS1 genes, including OAS1b, the flavivirus resistance gene (Flv r ] [5][6][7][8]. When stimulated by dsRNA, the functional OAS proteins produce a series of short 5′-phosphorylated, 2′,5′-linked oligoadenylates collectively referred to as 2-5A [p x 5′A(2′p5′A) n ; x = 1-3; n≥2] from ATP [9]. The first molecular clone for an OAS was obtained by Michel Revel's lab [10].…”

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A scientific journey through the 2-5A/RNase L system

Silverman

2007

Cytokine & Growth Factor Reviews

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The antiviral and antitumor actions of interferons are caused, in part, by a remarkable regulated RNA cleavage pathway known as the 2-5A/RNase L system. 2′-5′ linked oligoadenylates (2-5A) are produced from ATP by interferon-inducible synthetases. 2-5A activates pre-existing RNase L, resulting in the cleavage of RNAs within single-stranded regions. Activation of RNase L by 2-5A leads to an antiviral response, although precisely how this happens is a subject of ongoing investigations. Recently, RNase L was identified as the hereditary prostate cancer 1 gene. That finding has led to the discovery of a novel human retrovirus, XMRV. My scientific journey through the 2-5A system recounts some of the highlights of these efforts. Knowledge gained from studies on the 2-5A system could have an impact on development of therapies for important viral pathogens and cancer.Keywords 2-5A; RNase L; interferon; cancer; virus Background on the 2-5A/RNase L systemOver the past thirty-years, investigations into the mechanisms of interferon (IFN) action have elucidated how antiviral innate immunity operates within and between mammalian cells. The focus of my work over this period has been, and continues to be, probing the biology and biochemistry of the 2-5A/RNase L system, and studying its roles in health and disease. My scientific journey, from basic research to clinical studies, are summarized in this monograph. The 2-5A/RNase L system is one the principal pathways by which IFNs suppress viral infections. Exposure of cells to IFNs induces expression of genes that result in an "antiviral state". Type I IFNs bind to the IFN-α receptor 1 (IFNAR1) and IFNAR2 polypeptide chains on cell surfaces initiating JAK-STAT signaling to the IFN stimulated genes (ISGs) [1]. Included among over a hundred different ISGs are genes encoding 2-5A synthetases (OAS) [2,3]. The OAS genes are a family of ISGs that function in the 2-5A/RNase L system (Fig. 1). In humans there are three functional OAS genes (OAS1-3), resulting in 8 to 10 OAS isoforms due to alternative mRNA splicing [4]. In mice, in addition to OAS2 and OAS3 there are 7 separate OAS1 genes, including OAS1b, the flavivirus resistance gene (Flv r ] [5][6][7][8]. When stimulated by dsRNA, the functional OAS proteins produce a series of short 5′-phosphorylated, 2′,5′-linked oligoadenylates collectively referred to as 2-5A [p x 5′A(2′p5′A) n ; x = 1-3; n≥2] from ATP [9]. The first molecular clone for an OAS was obtained by Michel Revel's lab [10]. Biochemical characterization of OAS proteins by Ara Hovanessian's lab [11][12][13][14] and Ganes Sen's lab [15][16][17][18][19] and a crystal structure by Rune Hartmann and Vivien Yee (in collaboration with Ganes Sen and Just Justesen) [20] have led to functional and structural insight into the OAS family of 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, type...

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Section: Monitoring the Presence And Activation Of Rnase L In Intact mentioning

confidence: 99%

Section: Monitoring the Presence And Activation Of Rnase L In Intact mentioning

confidence: 99%

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A scientific journey through the 2-5A/RNase L system

Silverman

2007

Cytokine & Growth Factor Reviews

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“…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 L, that was activated by 2-5A [10].…”

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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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“…The 2-5A/RNase L pathway is a single-stranded RNA (ssRNA) decay pathway induced by IFNs: the 2-5A synthetases are induced by IFNs and upon activation by doublestranded RNA (dsRNA), convert ATP into a series of oligomers known as 2 0 -5 0 oligoadenylates (2-5A). 4,5 The 2-5A activates RNase L, a latent endoribonuclease, which inhibits protein synthesis by cleaving ssRNA. 6,7 RNase L plays a central role in IFNs cell growth inhibition and in IFN-induced apoptosis.…”

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Regulation of mitochondrial mRNA stability by RNase L is translation-dependent and controls IFNα-induced apoptosis

et al. 2007

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Interferons (IFNs) inhibit the growth of many different cell types by altering the expression of specific genes. IFNs activities are partly mediated by the 2 0 -5 0 oligoadenylates-RNase L RNA decay pathway. RNase L is an endoribonuclease requiring activation by 2 0 -5 0 oligoadenylates to cleave single-stranded RNA. Here, we present evidence that degradation of mitochondrial mRNA by RNase L leads to cytochrome c release and caspase 3 activation during IFNa-induced apoptosis. We identify and characterize the mitochondrial translation initiation factor (IF2mt) as a new partner of RNase L. Moreover, we show that specific inhibition of mitochondrial translation with chloramphenicol inhibits the IFNa-induced degradation of mitochondrial mRNA by RNase L. Finally, we demonstrate that overexpression of IF2mt in human H9 cells stabilizes mitochondrial mRNA, inhibits apoptosis induced by IFNa and partially reverses IFNa-cell growth inhibition. On the basis of our results, we propose a model describing how RNase L regulates mitochondrial mRNA stability through its interaction with IF2mt. Apoptosis is a regulated cell death process that plays a central role in the control of many physiological events. Cells die by apoptosis during embryonic development, tissue homeostasis or immune regulation and defects in the apoptotic pathway during these events can lead to excessive cell accumulation with dramatic consequences. 1-3 Interferons (IFNs) are among the regulators of apoptosis. They belong to a family of cytokines produced and secreted by mammalian cells in response to various inducers. They are negative regulators of cell proliferation through induction of cell-cycle arrest and apoptosis, but the mechanisms are not yet fully understood. The 2-5A/RNase L pathway is a single-stranded RNA (ssRNA) decay pathway induced by IFNs: the 2-5A synthetases are induced by IFNs and upon activation by doublestranded RNA (dsRNA), convert ATP into a series of oligomers known as 2 0 -5 0 oligoadenylates (2-5A). 4,5 The 2-5A activates RNase L, a latent endoribonuclease, which inhibits protein synthesis by cleaving ssRNA. 6,7 RNase L plays a central role in IFNs cell growth inhibition and in IFN-induced apoptosis. [8][9][10][11][12] Activation of RNase L causes caspase-dependent apoptosis accompanied by cytochrome c release from the mitochondria. 13 20 RNase L activity is regulated not only by 2-5A binding, but also by interaction with other proteins. It has been shown previously that RNase L can form a heterodimer with the RNase L inhibitor (RLI), a protein that inhibits 2-5A binding to RNase L, resulting in an inhibition of RNase L activity. 21,22 More recently, we demonstrated that RNase L interacts with the translation termination release factor eRF3/GSPT1 and that their interaction is important for its role in translation termination regulation. 23 We set out to identify other potential RNase L partners to better comprehend its mechanism of action. In the present study, a yeast two-hybrid screening, using human RNase L as bait identifies ...

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pppA2'p5'A2'p5'A: an inhibitor of protein synthesis synthesized with an enzyme fraction from interferon-treated cells.

Cited by 725 publications

References 17 publications

A scientific journey through the 2-5A/RNase L system

A scientific journey through the 2-5A/RNase L system

Diverse functions of RNase L and implications in pathology

Regulation of mitochondrial mRNA stability by RNase L is translation-dependent and controls IFNα-induced apoptosis

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