How Cells Respond to Interferons

Stark, George R.; Kerr, Ian M.; Williams, Bryan R.G.; Silverman, Robert H.; Schreiber, Robert D.

doi:10.1146/annurev.biochem.67.1.227

Cited by 3,630 publications

(3,267 citation statements)

References 322 publications

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“…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].…”

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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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: 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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“…Interferons (IFNs) are the prototype cytokines that activate a unique class of transcription factors known as STAT (signal transducers and activators of transcription) proteins (Horvath and Darnell, 1997;Leonard and O'Shea, 1998;Stark et al, 1998). As illustrated in Figure 3 for both Stat5a and Stat5b, STAT family proteins typically contain an aminoterminal region, followed by a coiled-coil region, a DNA binding domain (except Stat2), a linker region, an SH2 domain, a conserved tyrosine residue approximately 700 amino acids from the amino-terminus, and a carboxyl-terminal transactivation region.…”

Section: Stat Proteins and Their Activationmentioning

confidence: 99%

“…Activated Stat1 proteins then dissociate from the receptor, and the free, tyrosine-phosphorylated Stat1 monomers favor the formation of homodimers as they have a greater avidity for each other than for reassociating with the docking site on the receptor. Therefore, the SH2 domain on each STAT protein serves two roles (Horvath and Darnell, 1997;Leonard and O'Shea, 1998;Stark et al, 1998). First, it provides the ability for the STAT protein to dock on a phosphorylated tyrosine on the receptor.…”

Section: Stat Proteins and Their Activationmentioning

confidence: 99%

The role of Stat5a and Stat5b in signaling by IL-2 family cytokines

2000

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“…IFNg induces gene expression through the activation of various transcription factors including the interferonresponsive factor-1 (IRF-1), 20 which binds the interferonresponsive element (IRE) present in the promoter of IFNg-responsive genes. 20 To determine whether the secreted IFNg was biologically active, we investigated the expression of IRF-1 protein in HRE-IFN-Mf in response to PA or DFX stimulation (Figure 3a).…”

Section: Resultsmentioning

confidence: 99%

Picolinic acid- or desferrioxamine-inducible autocrine activation of macrophages engineered to produce IFNγ: an approach for gene therapy

et al. 2004

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Macrophage (Mf)-based vectors are highly mobile cellular shuttles designed to deliver therapeutic genes within the tissues. We engineered a mouse Mf cell line to express the murine interferon-g (IFNg) under the control of an inducible promoter containing the hypoxia-responsive element, which can be triggered by hypoxia and other stimuli. We show that this Mf vector can be induced to produce IFNg under normoxic conditions by stimulation with picolinic acid (PA), a catabolite of tryptophan, or desferrioxamine (DFX), an ironchelating drug. The Mf vector responds to IFNg with the induction of IRF-1 and of other IFNg-inducible genes, the expression of Ia antigens and induction of phagocytic activity.Inducible nitric oxygen synthase gene expression, nitric oxide production, as well as TNFa secretion were enhanced by PA or DFX as the sole stimuli. None of the above responses could be triggered individually by PA or DFX in control, normal Mf, indicating that the Mf vector overcame the need for costimulatory molecules derived from the immune system for its full activation. Furthermore, we demonstrate that extracellular iron can downregulate such response, thereby identifying an additional tool for the fine tuning of the Mf vector response to stimulation.

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How Cells Respond to Interferons

Cited by 3,630 publications

References 322 publications

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

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

The role of Stat5a and Stat5b in signaling by IL-2 family cytokines

Picolinic acid- or desferrioxamine-inducible autocrine activation of macrophages engineered to produce IFNγ: an approach for gene therapy

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