Gene structure of the murine 2′-5′-oligoadenylate synthetase family

Eskildsen, Signe Janum; Hartmann, Rune; Kjeldgaard, Niels Ole; Justesen, Just

doi:10.1007/s00018-002-8499-2

Cited by 50 publications

(40 citation statements)

References 20 publications

(21 reference statements)

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“…Virus-Production of low passaged WNV strain IS-98-ST1 (GenBank TM accession number AF 481864) on mosquito Aedes pseudoscutellaris (AP61) cell monolayers, purification on sucrose gradients, and virus titration by focus immunodetection assay were performed as previously described (10). Virus titers are expressed as focus forming units.…”

Section: Methodsmentioning

confidence: 99%

The 2′,5′-Oligoadenylate Synthetase 1b Is a Potent Inhibitor of West Nile Virus Replication Inside Infected Cells

Kajaste‐Rudnitski

Mashimo

Frenkiel

et al. 2006

Journal of Biological Chemistry

103

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The 2,5-oligoadenylate synthetase (OAS) proteins associated with endoribonuclease RNase L are components of the interferonregulated OAS/RNase L system, which is an RNA decay pathway known to play an important role in the innate antiviral immunity. A large body of evidence suggests a critical role for the 1b isoform of the mouse Oas gene (Oas1b) in resistance to West Nile virus (WNV) infection in vivo. WNV is a positive, single-stranded RNA virus responsible for severe encephalitis in a large range of animal species and humans. To investigate the molecular basis for the sensitivity of WNV to the Oas1b antiviral pathway, we established a stable mouse fibroblastic cell clone that up-regulates Oas1b protein expression under the control of the Tet-Off expression system. We showed that murine cells respond to Oas1b expression by efficiently inhibiting WNV replication. The antiviral action of Oas1b was essentially restricted to the early stages in virus life cycle. We found that the inability of WNV to productively infect the Oas1b-expressing cells was attributable to a dramatic reduction in positive-stranded viral RNA level. Thus, Oas1b represents an antiviral pathway that exerts its inhibitory effect on WNV replication by preventing viral RNA accumulation inside infected cells. The emergence of virulent variant of West Nile virus (WNV)6 has been associated with a dramatic increase in severity of infection in humans, thus drawing the attention to West Nile illness as a public health concern (1). WNV is an enveloped, plus-stranded RNA virus that belongs to the flavivirus genus (family Flaviviridae) (2). WNV infects the central nervous system and causes viral encephalitis in a large range of animal species (1). The virion is composed of three structural proteins: C (core protein), M (membrane protein), and E (envelope protein). Translation of genomic RNA results in the synthesis of structural proteins C, prM (the intracellular precursor of M) and E, and seven non-structural (NS) proteins NS1 to NS5 (2). In the cytoplasm, the RNA replication begins with the synthesis of negative-and positive-stranded genome-length RNA (2).The rapid initiation of innate antiviral mechanisms mediated by Type-I IFNs (IFN-␣/␤) may be essential for protection against WNV infection (3-5). We reported that IFN-␣/␤ receptor-deficient mice have an increased susceptibility to WNV as compared with immunocompetent mice (6). IFN-␣ and -␤ are able to trigger the activation of a specific signal transduction pathway leading to induction of IFN-stimulated genes that are responsible for the establishment of an antiviral state (7). The IFN-induced proteins believed to affect virus replication in single cells are the RNA-specific adenosine deaminase, the proteins of the Mx family, the double-stranded RNA-dependent protein kinase, and the 2Ј,5Ј-oligoadenylate synthetase (OAS) family associated to endoribonuclease RNase L (OAS/RNase L system) (7).The OAS/RNase L system is an RNA decay pathway known to play an important role in the established endogenous antiv...

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Section: Methodsmentioning

confidence: 99%

The 2′,5′-Oligoadenylate Synthetase 1b Is a Potent Inhibitor of West Nile Virus Replication Inside Infected Cells

Kajaste‐Rudnitski

Mashimo

Frenkiel

et al. 2006

Journal of Biological Chemistry

103

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“…3B). To abolish the catalytic activity of Oasl2, we then mutated two of the three conserved Asp residues in its core catalytic triad (19) to create the mutant designated "DADA." As shown (Fig.…”

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confidence: 99%

2′-5′-Oligoadenylate Synthetase-Like Protein Inhibits Respiratory Syncytial Virus Replication and Is Targeted by the Viral Nonstructural Protein 1

Dhar

Cuevas

Goswami

et al. 2015

J Virol

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2=-5=-Oligoadenylate synthetase-like protein (OASL) is an interferon-inducible antiviral protein.Here we describe differential inhibitory activities of human OASL and the two mouse OASL homologs against respiratory syncytial virus (RSV) replication. Interestingly, nonstructural protein 1 (NS1) of RSV promoted proteasome-dependent degradation of specific OASL isoforms. We conclude that OASL acts as a cellular antiviral protein and that RSV NS1 suppresses this function to evade cellular innate immunity and allow virus growth. C ellular innate immunity against virus infection is primarily mediated by type I interferons (IFNs). In turn, the IFNs exert their pleiotropic effects through the induction of a variety of IFNstimulated genes (ISGs) (1-4). Although the general antiviral roles of several ISGs have been demonstrated, the roles of individual ISGs and their effect on specific viruses have remained largely unidentified (5-9). On the other hand, the coevolution of the host and the virus has resulted in viral strategies to evade the host IFN response by targeting ISGs and other IFN pathway proteins (10). Oligoadenylate synthetases (OAS) are a family of ISGs characterized by their ability to synthesize 2=-5=-oligoadenylate (2-5A), which induces RNA degradation by activating RNase L (11, 12). Human oligoadenylate synthetase-like protein (OASL) is related to the OAS family by its N-terminal OAS-like domain but is devoid of 2-5A synthetase activity. Additionally, OASL contains two tandem ubiquitin-like (UBL) domains in the C terminus, which are absent in any of the other members of the OAS family (12-15). OASL is directly and rapidly induced by virus infection via interferon regulatory factor 3 (IRF3) as well as by IFN signaling (1,12,16,17). Unlike in humans, two OASL isoforms have been identified in the mouse, Oasl1 and Oasl2. We have recently described the (18), were grown in monolayers on coverslips and infected with RSV Long at a multiplicity of infection of 3. At 18 h postinfection, cells were fixed and immunostained with mouse anti-RSV nucleoprotein (N) antibody (Abnova clone B023), followed by Alex Fluor 610-conjugated donkey anti-mouse IgG (Life Technologies). Images were captured in a Nikon AIRSI spectral confocal microscope system. (B) (Top) The same cell lines were infected as described above, and the total cell lysates were analyzed by immunoblotting using the same primary antibody described above and horseradish peroxidase (HRP)-conjugated secondary antibody, followed by ECL (enhanced chemiluminescence) detection. Actin is the loading control. (Bottom) Total RNA isolated from parallel cultures was subjected to quantitative reverse transcription-PCR (qRT-PCR), as described previously (38). The primers, synthesized by Integrated DNA Technologies (Coralville, IA), were as follows. RSV N gene, forward 5=-TGCAGGGCAAGTGATGTTAC-3=, and reverse, 5=-TTCCATTTCTGCTTGCACAC-3=; actin, forward, 5=-AGAAAATCTGGCACCACACC-3=, and reverse, 5=-GGGGTGTTGAAGGTCTCAAA-3=. A portion of the PCR sample was analyzed on 1.5% agarose...

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“…Recently, a gene family of eight members, all coding for a variant of oligoadenylate synthetase 1 (OAS1, A to H), has been characterized and mapped to a narrow chromosomal region in the vicinity of Flv (8,15). Concurrently, a gene family member, Oas1b, which carries a premature stop codon in the fourth exon in susceptible mouse strains only, has been identified as a possible Flv candidate (3,24,27).…”

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confidence: 99%

“…It is well established that the genes of the Oas1 family are both alpha/beta interferon (IFN-␣/␤) and poly(I-C) (pIC) inducible, potentially contributing to the cellular antiviral effects via the ubiquitous OAS1/RNase L pathway (8,15). Although genetically determined host resistance to flaviviruses was shown to be IFN-␣/␤ independent following IFN-␣/␤ depletion (2), pretreatment with IFN-␣/␤ in a separate study has on the contrary induced a significant enhancement of flavivirus resistance both in vivo and in vitro (13).…”

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confidence: 99%

Differential Induction of Antiviral Effects against West Nile Virus in Primary Mouse Macrophages Derived from Flavivirus-Susceptible and Congenic Resistant Mice by Alpha/Beta Interferon and Poly(I-C)

Pantelic

Sivakumaran²,

Urosevic³

2005

J Virol

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Together with hepatitis C virus and Pestivirus genera, flaviviruses belong to the Flaviviridae family of positive singlestranded RNA viruses. The genus Flavivirus consists of a number of medically important viruses such as yellow fever, West Nile (WN), Japanese encephalitis (JE), Murray Valley encephalitis (MVE), and dengue (DEN) viruses (25). While yellow and dengue fevers may deteriorate into life-threatening conditions, an acute, apparent infection with encephalitogenic flaviviruses rapidly progresses to lethal flavivirus-induced encephalitis in almost one-quarter of infected patients (21). The recent emergence of the flavivirus WN virus in New York State and its rapid spread to surrounding states in North America is an alarming event (29), in addition to the long-standing risk imposed by JE and DEN viruses in other parts of world. There are almost 20 serologically unrelated flaviviruses implicated in human diseases for which there is no vaccine or antiviral treatment available. The majority of these viruses are arthropod borne with an amplifying vertebrate host serving as a natural reservoir and a mosquito or tick vector needed for further dissemination of the virus in nature. Although humans often represent an accidental dead-end host for the virus (21), the incidence of flavivirus-mediated diseases in human populations may expand to either seasonal outbreaks or even localized epidemics causing a major concern to public health. In the absence of an adequate vaccination program, the host natural resistance to flaviviruses as well as development of appropriate antiviral therapies gain importance as alternative approaches for the prevention of diseases caused by flaviviruses (3, 44).Involvement of genetic factors in the resistance to flavivirus infection is difficult to estimate in humans. In contrast, mice carry a genetic trait conferring resistance to flaviviruses that is widely distributed among wild mice populations and rare among laboratory mouse strains (34). Only a few strains of laboratory mice have preserved this trait; among these are PRI, CAST/Ei, CASA/Rk, and MOLD/Rk (34). Some of these strains have been used for backcross breeding to flavivirussusceptible C3H/He mice, resulting in the development of new congenic flavivirus-resistant mouse strains: C3H.PRI-Flv r mice, which carry the resistance allele from outbred PRI mice (12); C3H.M. domesticus-Flv r -like mice, which are derived from flavivirus-resistant wild Mus musculus domesticus; and C3H.MOLDFlv mr mice, which carry the resistance allele from MOLD/Rk mice (38,45).Flavivirus resistance in mice is controlled by a single locus, flavivirus resistance (Flv), on mouse chromosome 5 (31, 44). Although we have defined a narrow region on mouse chromosome 5 that carries the Flv locus by low-and high-resolution genetic and physical mapping, those studies have not clearly identified the critical boundaries of the Flv segment within a larger genomic region of ϳ31 centimorgans that is polymorphic between susceptible C3H/He and resistant C3H.PRI-Flv r mice ...

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Gene structure of the murine 2′-5′-oligoadenylate synthetase family

Cited by 50 publications

References 20 publications

The 2′,5′-Oligoadenylate Synthetase 1b Is a Potent Inhibitor of West Nile Virus Replication Inside Infected Cells

The 2′,5′-Oligoadenylate Synthetase 1b Is a Potent Inhibitor of West Nile Virus Replication Inside Infected Cells

2′-5′-Oligoadenylate Synthetase-Like Protein Inhibits Respiratory Syncytial Virus Replication and Is Targeted by the Viral Nonstructural Protein 1

Differential Induction of Antiviral Effects against West Nile Virus in Primary Mouse Macrophages Derived from Flavivirus-Susceptible and Congenic Resistant Mice by Alpha/Beta Interferon and Poly(I-C)

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