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

Abstract

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...

Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: An Update

“…However, the transcriptional signalling pathways mediated by 2-5a activation of RNase L is at present not completely understood. Moreover RNase L-deficient mice retained a significant IFN antiviral response (26), and with the current data available it is not possible to ascertain an association between RNase L variants described in some CFS patients and the disease.…”

Inhibition of Xenotropic Murine Leukemia Virus-Related Virus by APOBEC3 Proteins and Antiviral Drugs

“…In 2006, for the first time, a gammaretrovirus was isolated from human tissues and was named xenotropic murine leukemia virus-related virus (XMRV) (63). The virus was discovered to be prevalent in prostate cancer tissues derived from patients carrying a mutation in the RNASEL gene, an important player in the interferon-mediated suppression of viral infection in host target cells (48,53,54). A recent study found XMRV in several prostate cancer samples with the same prevalence for patients with and without the RNASEL mutation and suggested that XMRV infection may be associated with nearly 30% of all prostate cancers (51).…”

Roles of Vaccinia Virus Genes E3L and K3L and Host Genes PKR and RNase L during Intratracheal Infection of C57BL/6 Mice

“…OAS is activated by double-stranded RNA initiation or highly structured RNA, in a process that results in the activation of RNase L and ultimately in RNA degradation. Both PKR and RNase L/2Ј-5Ј oligoadenylate system proteins and functions have been reviewed recently (26,34,52,55,56,64,65,66,72). It is now known that at least two virus-carried genes, the E3L and K3L genes, protect the virus from the effects of interferon and that their encoded proteins interact with host RNase L and PKR proteins (10,11,19,64).…”