Interferon action—sequence specificity of the ppp(A2′p)nA-dependent ribonuclease

Wreschner, Daniel H.; McCauley, John W.; Skehel, J.J.; Kerr, Ian M.

doi:10.1038/289414a0

Cited by 313 publications

(193 citation statements)

References 22 publications

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“…Detection of activated RNase L within cells could be conveniently monitored by the specific breakdown in the rRNA [44]. By demonstrating IFNand virus-dependent activation of both OAS and RNase L, these and prior studies (with Bryan Williams, Matty Knight, Jane Cayley, Danny Wreschner and other members of the Kerr lab) firmly established the 2-5A/RNase L system as a participant in the antiviral actions of IFNs [21,28,45,46].…”

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

confidence: 79%

“…To do so, 2-5A must have at least one 5′-phosphoryl group, the internucleotide linkages must be 2′ to 5′ and the nucleotides must by adenylyl residues for optimal activity [27]. RNase L is activated by subnanomolar levels of 2-5A resulting in the cleavage of single-stranded regions of RNA, preferentially after UpUp and UpAp dinucleotides [28,29]. In addition, single-stranded regions of RNAs that are partially double-stranded are preferentially cleaved by RNase L [30].…”

Section: Background On the 2-5a/rnase L Systemmentioning

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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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: 79%

Section: Background On the 2-5a/rnase L Systemmentioning

confidence: 99%

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

Silverman

2007

Cytokine & Growth Factor Reviews

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“…In brief, IFN induces the transcription of several 2-5A synthetase genes whose protein products are in turn activated by dsRNA and produce 5′-triphosphorylated, 2′,5′-oligoadenylates (2-5A) from ATP [11]. 2-5A bind specifically to RNase L, which is activated to cleave single stranded RNAs at UpN (mainly UpU and UpA) sequences in single-stranded regions of RNA [12,13]. The only known function of 2-5A is to bind and activate RNase L. 2-5A is very unstable in cells and in serum.…”

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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“…poly(U) specificity, slight activation by (2' -5') (A)4, the nuclease described in this contribution resembles the ~pp(A2'p)~A-dependent endoribonuclease. This enzyme, in the presence of divalent cations [37], degrades only poly(U); poly(A), poly(G) and poly(C) [38] are not substrates for the enzyme. The endoribonuclease was determined not to be permanently activated by (2' -5') (A)n [39,38].…”

Section: Discussionmentioning

confidence: 99%

“…This enzyme, in the presence of divalent cations [37], degrades only poly(U); poly(A), poly(G) and poly(C) [38] are not substrates for the enzyme. The endoribonuclease was determined not to be permanently activated by (2' -5') (A)n [39,38]. However, from the purification methods described [37,40] no hint can be drawn that the ~pp(A2'p)~A-dependent endoribonuclease is RNP-associated.…”

Section: Discussionmentioning

confidence: 99%

Association of a polyuridylate‐specific endoribonuclease with small nuclear ribonucleo‐proteins which had been isolated by affinity chromatography using antibodies from a patient with systemic lupus erythematosus

Bachmann

Trautmann

Messer

et al. 1983

European Journal of Biochemistry

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Immunoglobulins, containing antibodies against U1-snRNP, have been prepared from a patient with systemic lupus erythematosus. After coupling these antibodies to a Sepharose matrix, U-snRNPs have been isolated and purified from rat liver nuclei by use of immunoaffinity chromatography. The resulting RNPs had the typical protein pattern of U-snRNPs and a sedimentation coefficient of 12 S. The U-snRNP preparation was associated with an endoribonuclease which required Mg2+ for optimal activity. The enzyme, with an pH optimum of 6.2, degraded only poly(U). Other single-stranded polyribo-and polydeoxyribonucleotides, tRNA, as well as double-stranded RNA and DNA were not digested. The products of a terminal digestion are (U)6-12 with 3'-OH and 5'-P termini. The possible involvement of this endoribonuclease in the splicing of hnRNA is discussed.Most eukaryotic genes, besides exon regions represented in the mRNA, also contain intron sequences. These are removed in the nucleus from the primary transcript (hnRNA) by splicing reactions [l]. It is not yet clear at which time during the overall course of post-transcriptional processing of mRNA splicing occurs [2,3]. Some evidence is available indicating that the poly(A) segment of mRNA [2] and/or nucleoplasmic U-snRNPs [4] orient the splicing of mRNA precursors. Comparison of the consensus sequences at RNA splicing sites in pre-mRNA with sequences in U1 RNA revealed an exact complementarity [5,6], suggesting a model in which U1 RNP is one recognition component of the nuclear RNA splicing apparatus. This assumption is supported by the finding that snRNAs are directly associated with hnRNA [7,8]. Moreover, it has been demonstrated that lupus antiserum, which precipitates U1 RNP, inhibits splicing of adenovirus mRNA by isolated HeLa cell nuclei [9]. Up to now, enzymes involved in mRNA splicing have not been characterized. In a recent contribution [lo] we reported that endoribonuclease VII is a candidate for a splicing enzyme in a hypothesized poly(A)-mediated splicing process. This enzyme was found to be modulated by poly(A) and is able to recognize oligo(U) sequences.Supposing that U1-snRNA is essential for the splicing reactions, it seems reasonable to search also for an enyzme(s)

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Interferon action—sequence specificity of the ppp(A2′p)nA-dependent ribonuclease

Cited by 313 publications

References 22 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

Association of a polyuridylate‐specific endoribonuclease with small nuclear ribonucleo‐proteins which had been isolated by affinity chromatography using antibodies from a patient with systemic lupus erythematosus

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