Interferon, double-stranded RNA and mRNA degradation

Sen, Ganes C.; Lebleu, Bernard; Brown, Gene M.; Kawakita, Masao; Slattery, Elizabeth; Lengyel, Péter

doi:10.1038/264370a0

Cited by 104 publications

(36 citation statements)

References 15 publications

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“…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.…”

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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Section: I) Introductionmentioning

confidence: 99%

Diverse functions of RNase L and implications in pathology

Bisbal

Silverman

2007

Biochimie

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“…Ribosomal and viral RNAs are reportedly the first targets of RNase L. Recent evidence has shown that RNase L plays an important role in the stability of several gene products, including IFN-induced genes such as ISG 43 , ISG 15 (4) and PKR (5) in RNase L null cells, MyoD mRNA in myocytes (6), mitochondrial mRNAs in H 9 lymphocytes (7) and mitochondrial DNA-encoded mRNA (mt-mRNA) in monensin-treated mouse embryonic fibroblasts (MEFs) (8). Interestingly, activated RNase L selectively targets viral RNA in intact cells and the action is 2-5A level dependent (9).…”

Section: Mechanism Of Actionmentioning

confidence: 99%

“…However, IFN treatment extended survival to EMCV infection of both the RNase L wild-type and knockout mice, suggesting multiple and overlapping antiviral pathways of IFN. RNase L has been shown to have antiviral effects on other viruses such as vesicular stomatitis virus, vaccinia virus, HIV-1, West Nile virus, herpes simplex virus (HSV), and SV40 (15).…”

Section: Antiviral Activity Of Rnase Lmentioning

confidence: 99%

RNase L: Its biological roles and regulation

Liang

Quirk

Zhou

2006

IUBMB Life (International Union of Biochemistry and Molecular B

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Summary2 0 -5 0 oligoadenylate-dependent ribonuclease L (RNase L) is one of the key enzymes involved in the function of interferons (IFNs), a family of cytokines participating in innate immunity against viruses and other microbial pathogens. Upon binding with its activator, 5 0 -phosphorylated, 2 0 -5 0 linked oligoadenylates (2-5A), RNase L degrades single-stranded viral and cellular RNAs and thus plays an important role in the antiviral and antiproliferative functions of IFNs. In recent years, evidence has revealed that RNase L displays a broad range of biological roles which are summarized in this review.

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“…This is manifested only if the extracts are supplemented with double-stranded RNA and ATP (4,5). These agents are needed for the activation of an endonuclease activity,* but do not have to be present during the cleavage of RNA (6,7). 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).…”

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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%