Interferon-mediated protein kinase and low-molecular-weight inhibitor of protein synthesis

Roberts, Walden K.; Hovanessian, Ara G.; Brown, Ronald E.; Clemens, Michael J.; Kerr, Ian M.

doi:10.1038/264477a0

Cited by 416 publications

(206 citation statements)

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“…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]. My transition was an easy one in that I was immediately able to go to work because all of the cell-free system components were in place in Eppendorf tubes in the −70C° freezer.…”

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

confidence: 99%

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%

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 Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication.…”

Section: I) Introductionmentioning

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 "nuclease activators" that mediate the activation are 2'-5' linked oligoadenylates [(2'-5')An] with 5'-terminal triphosphate or diphosphate (8)(9)(10)(11)(12)(13)(14)(15)(16). This series of compounds was originally discovered as an inhibitor of protein synthesis that is formed from ATP in extracts of various interferon-treated cells (and in lysates from rabbit reticulocytes not treated with interferon) in the presence of double-stranded RNA (17)(18)(19)(20). The level of the enzyme catalyzing (2'-5')An synthesis is greatly increased in cells upon treatment with interferon (8,(21)(22)(23).…”

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confidence: 99%

“…The enzyme was partially purified from mouse Ehrlich ascites tumor cells and L cells (8,11,12). In (25), the protein fraction tested for endonuclease activity (in [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] Ml), and the specified amount of (2'-5')An preparation I, II, or III if so indicated. After incubation at 30°C for 1 hr, the reaction was terminated and the reaction mixture was analyzed by polyacrylamide gel electrophoresis and radioautography.…”

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confidence: 99%