scholarly journals ABCE1 Acts as a Positive Regulator of Exogenous RNA Decay

Viruses ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 174
Author(s):  
Takuto Nogimori ◽  
Koichi Ogami ◽  
Yuka Oishi ◽  
Ryoya Goda ◽  
Nao Hosoda ◽  
...  
Keyword(s):  
Rna Decay ◽  
Control Factor ◽  
Rnase L ◽  
Oligoadenylate Synthetase ◽  
Positive Regulator ◽  
Rnase L Inhibitor ◽  
L System ◽  
Exogenous Rna ◽  
Rna Quality Control ◽  
Pathogenic Viruses

The 2′-5′-oligoadenylate synthetase (OAS)/RNase L system protects hosts against pathogenic viruses through cleavage of the exogenous single-stranded RNA. In this system, an evolutionally conserved RNA quality control factor Dom34 (known as Pelota (Pelo) in higher eukaryotes) forms a surveillance complex with RNase L to recognize and eliminate the exogenous RNA in a manner dependent on translation. Here, we newly identified that ATP-binding cassette sub-family E member 1 (ABCE1), which is also known as RNase L inhibitor (RLI), is involved in the regulation of exogenous RNA decay. ABCE1 directly binds to form a complex with RNase L and accelerates RNase L dimer formation in the absence of 2′-5′ oligoadenylates (2-5A). Depletion of ABCE1 represses 2-5A-induced RNase L activation and stabilizes exogenous RNA to a level comparable to that seen in RNase L depletion. The increased half-life of the RNA by the single depletion of either protein is not significantly affected by the double depletion of both proteins, suggesting that RNase L and ABCE1 act together to eliminate exogenous RNA. Our results indicate that ABCE1 functions as a positive regulator of exogenous RNA decay rather than an inhibitor of RNase L.

scholarly journals Activation and Antagonism of the OAS–RNase L Pathway

Proceedings ◽  
2020 ◽  
Vol 50 (1) ◽  
pp. 14
Author(s):  
Susan R. Weiss
Keyword(s):  
Cell Death ◽  
Antiviral Activity ◽  
Apoptotic Cell ◽  
Early Response ◽  
Apoptotic Cell Death ◽  
Rnase L ◽  
Oligoadenylate Synthetase ◽  
Viral Genomes ◽  
L System ◽  
Infected Cells

The oligoadenylate synthetase–ribonuclease L (OAS–RNase L) system is a potent antiviral pathway that severely limits the pathogenesis of many viruses. Upon sensing dsRNA, OASs produce 2′,5′-oligoadenylates (2-5A) that activate RNase L to cleave both host and viral single-stranded RNA, thereby limiting protein production, virus replication and spread, leading to apoptotic cell death. Endogenous host dsRNA, which accumulates in the absence of adenosine deaminase acting on RNA (ADAR)1, can also activate RNase L and lead to apoptotic cell death. RNase L activation and antiviral activity during infections with several types of viruses in human and bat cells is dependent on OAS3 but independent of virus-induced interferon (IFN) and, thus, RNase L can be activated even in the presence of IFN antagonists. Differently from other human viruses examined, Zika virus is resistant to the antiviral activity of RNase L and instead utilizes RNase L to enhance its replication factories to produce more infectious virus. Some betacoronaviruses antagonize RNase L activation by expressing 2′,5′-phosphodiesterases (PDEs) that cleave 2-5A and thereby antagonize activation of RNase L. The best characterized of these PDEs is the murine coronavirus (MHV) NS2 accessory protein. Enzymatically active NS2 is required for replication in myeloid cells and in the liver. Interestingly, while wild type mice clear MHV from the liver by 7–10 days post-infection, RNase L knockout mice fail to effectively clear MHV, probably due to diminished apoptotic death of infected cells. We suggest that RNase L antiviral activity stems from direct cleavage of viral genomes and cessation of protein synthesis as well as through promoting death of infected cells, limiting the spread of virus. Importantly, OASs are pattern recognition receptors and the OAS–RNase L pathway is a primary innate response pathway to viruses, capable of early response, coming into play before IFN is induced or when the virus shuts down IFN signaling.

scholarly journals Involvement of the Interferon-Regulated Antiviral Proteins PKR and RNase L in Reovirus-Induced Shutoff of Cellular Translation

2005 ◽  
Vol 79 (4) ◽  
pp. 2240-2250 ◽  
Author(s):  
Jennifer A. Smith ◽  
Stephen C. Schmechel ◽  
Bryan R. G. Williams ◽  
Robert H. Silverman ◽  
Leslie A. Schiff
Keyword(s):  
Antiviral Effect ◽  
Cellular Protein ◽  
Dependent Manner ◽  
Rnase L ◽  
Oligoadenylate Synthetase ◽  
L System ◽  
Cellular Translation ◽  
Host Shutoff ◽  
Reovirus Replication ◽  
Biochemical Analyses

ABSTRACT Cellular translation is inhibited following infection with most strains of reovirus, but the mechanisms responsible for this phenomenon remain to be elucidated. The extent of host shutoff varies in a strain-dependent manner; infection with the majority of strains leads to strong host shutoff, while infection with strain Dearing results in minimal inhibition of cellular translation. A genetic study with reassortant viruses and subsequent biochemical analyses led to the hypothesis that the interferon-induced, double-stranded RNA-activated protein kinase, PKR, is responsible for reovirus-induced host shutoff. To directly determine whether PKR is responsible for reovirus-induced host shutoff, we used a panel of reovirus strains and mouse embryo fibroblasts derived from knockout mice. This approach revealed that PKR contributes to but is not wholly responsible for reovirus-induced host shutoff. Studies with cells lacking RNase L, the endoribonuclease component of the interferon-regulated 2′,5′-oligoadenylate synthetase-RNase L system, demonstrated that RNase L also down-regulates cellular protein synthesis in reovirus-infected cells. In many viral systems, PKR and RNase L have well-characterized antiviral functions. An analysis of reovirus replication in cells lacking these molecules indicated that, while they contributed to host shutoff, neither PKR nor RNase L exerted an antiviral effect on reovirus growth. In fact, some strains of reovirus replicated more efficiently in the presence of PKR and RNase L than in their absence. Data presented in this report illustrate that the inhibition of cellular translation following reovirus infection is complex and involves multiple interferon-regulated gene products. In addition, our results suggest that reovirus has evolved effective mechanisms to avoid the actions of the interferon-stimulated antiviral pathways that include PKR and RNase L and may even benefit from their expression.

scholarly journals Specific Inhibition of the PKR-Mediated Antiviral Response by the Murine Cytomegalovirus Proteins m142 and m143

2008 ◽  
Vol 83 (3) ◽  
pp. 1260-1270 ◽  
Author(s):  
Matthias Budt ◽  
Lars Niederstadt ◽  
Ralitsa S. Valchanova ◽  
Stipan Jonjić ◽  
Wolfram Brune
Keyword(s):  
Protein Synthesis ◽  
Antiviral Response ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Murine Cytomegalovirus ◽  
Rnase L ◽  
Oligoadenylate Synthetase ◽  
Eif2α Phosphorylation ◽  
L System ◽  
Simplex Virus

ABSTRACT Double-stranded RNA (dsRNA) produced during viral infection activates several cellular antiviral responses. Among the best characterized is the shutoff of protein synthesis mediated by the dsRNA-dependent protein kinase (PKR) and the oligoadenylate synthetase (OAS)/RNase L system. As viral replication depends on protein synthesis, many viruses have evolved mechanisms for counteracting the PKR and OAS/RNase L pathways. The murine cytomegalovirus (MCMV) proteins m142 and m143 have been characterized as dsRNA binding proteins that inhibit PKR activation, phosphorylation of the translation initiation factor eIF2α, and a subsequent protein synthesis shutoff. In the present study we analyzed the contribution of the PKR- and the OAS-dependent pathways to the control of MCMV replication in the absence or presence of m142 and m143. We show that the induction of eIF2α phosphorylation during infection with an m142- and m143-deficient MCMV is specifically mediated by PKR, not by the related eIF2α kinases PERK or GCN2. PKR antagonists of vaccinia virus (E3L) or herpes simplex virus (γ34.5) rescued the replication defect of an MCMV strain with deletions of both m142 and m143. Moreover, m142 and m143 bound to each other and interacted with PKR. By contrast, an activation of the OAS/RNase L pathway by MCMV was not detected in the presence or absence of m142 and m143, suggesting that these viral proteins have little or no influence on this pathway. Consistently, an m142- and m143-deficient MCMV strain replicated to high titers in fibroblasts lacking PKR but did not replicate in cells lacking RNase L. Hence, the PKR-mediated antiviral response is responsible for the essentiality of m142 and m143.

scholarly journals Down-regulation of ABCE1 inhibits temozolomide resistance in glioma through the PI3K/Akt/NF-κB signaling pathway

2018 ◽  
Vol 38 (6) ◽  
Author(s):  
Peng Zhang ◽  
Xiao-Bing Chen ◽  
Bing-Qian Ding ◽  
Hong-Lin Liu ◽  
Tao He
Keyword(s):  
Glioma Cells ◽  
Specific Effect ◽  
Rnase L ◽  
Down Regulation ◽  
Rnase L Inhibitor ◽  
L System ◽  
Promising Target ◽  
Wide Range

The ATP binding cassette (ABC) E1 (ABCE1), a member of the ABC family, was originally described as the RNase L inhibitor. Through forming a heterodimer with RNase L, ABCE1 participates in the negative regulation of the 2-5A/RNase L system and thus mediates a wide range of biological functions. Recent evidence has shown the new roles of ABCE1 in tumorigenesis. However, there have been no investigations on the specific effect of ABCE1 on glioma. In the present study, we examined the expression pattern and possible role of ABCE1 in glioma. Our study demonstrated that ABCE1 was up-regulated in glioma tissues and cell lines. Down-regulation of ABCE1 inhibited temozolomide (TMZ) resistance of glioma cells in vitro and in vivo. In addition, we found that the PI3K/Akt/NF-κB pathway was involved in ABCE1-mediated chemoresistance of glioma cells. Taken together, our study suggested ABCE1 as a promising target for glioma chemotherapy.

Clinical relevance of the 2′–5′-oligoadenylate synthetase/RNase L system for treatment response in chronic hepatitis C

2009 ◽  
Vol 50 (1) ◽  
pp. 49-58 ◽  
Author(s):  
Ulrike Mihm ◽  
Oliver Ackermann ◽  
Christoph Welsch ◽  
Eva Herrmann ◽  
Wolf Peter Hofmann ◽  
...  
Keyword(s):  
Chronic Hepatitis ◽  
Hepatitis C ◽  
Treatment Response ◽  
Chronic Hepatitis C ◽  
Clinical Relevance ◽  
Rnase L ◽  
Oligoadenylate Synthetase ◽  
L System

scholarly journals Heterozygous OAS1 gain-of-function variants cause an autoinflammatory immunodeficiency

2021 ◽  
Vol 6 (60) ◽  
pp. eabf9564
Author(s):  
Thomas Magg ◽  
Tsubasa Okano ◽  
Lars M. Koenig ◽  
Daniel F.R. Boehmer ◽  
Samantha L. Schwartz ◽  
...  
Keyword(s):  
B Cells ◽  
Hematopoietic Cell Transplantation ◽  
De Novo ◽  
Dynamics Simulation ◽  
Recurrent Fever ◽  
Type I ◽  
Rnase L ◽  
Oligoadenylate Synthetase ◽  
Gain Of Function ◽  
Translational Arrest

Analysis of autoinflammatory and immunodeficiency disorders elucidates human immunity and fosters the development of targeted therapies. Oligoadenylate synthetase 1 is a type I interferon–induced, intracellular double-stranded RNA (dsRNA) sensor that generates 2′-5′-oligoadenylate to activate ribonuclease L (RNase L) as a means of antiviral defense. We identified four de novo heterozygous OAS1 gain-of-function variants in six patients with a polymorphic autoinflammatory immunodeficiency characterized by recurrent fever, dermatitis, inflammatory bowel disease, pulmonary alveolar proteinosis, and hypogammaglobulinemia. To establish causality, we applied genetic, molecular dynamics simulation, biochemical, and cellular functional analyses in heterologous, autologous, and inducible pluripotent stem cell–derived macrophages and/or monocytes and B cells. We found that upon interferon-induced expression, OAS1 variant proteins displayed dsRNA-independent activity, which resulted in RNase L–mediated RNA cleavage, transcriptomic alteration, translational arrest, and dysfunction and apoptosis of monocytes, macrophages, and B cells. RNase L inhibition with curcumin modulated and allogeneic hematopoietic cell transplantation cured the disorder. Together, these data suggest that human OAS1 is a regulator of interferon-induced hyperinflammatory monocyte, macrophage, and B cell pathophysiology.

Phosphorothioate Analogs of 2–5A: Elucidation of the Stereochemical Course of the Enzymes of the 2–5A Synthetase/RNase L System

1987 ◽  
Vol 6 (1-2) ◽  
pp. 173-184 ◽  
Author(s):  
Katalin Karikó ◽  
Shu Wu Li ◽  
Robert W. Sobol ◽  
Lorraine Suhadolnik ◽  
Nancy L. Reichenbach ◽  
...  
Keyword(s):  
Rnase L ◽  
L System

Introns encode dsRNAs undetected by RIG-I/MDA5/interferons and sensed via RNase L

2021 ◽  
Vol 118 (46) ◽  
pp. e2102134118
Author(s):  
Alisha Chitrakar ◽  
Kristina Solorio-Kirpichyan ◽  
Eliza Prangley ◽  
Sneha Rath ◽  
Jin Du ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Immune Responses ◽  
Innate Immune ◽  
Rna Decay ◽  
Antiviral Defense ◽  
Rnase L ◽  
Innate Immune Responses ◽  
Double Stranded Rna ◽  
Turn On ◽  
Nuclear Rna

Double-stranded RNA (dsRNA), a hallmark viral material that activates antiviral interferon (IFN) responses, can appear in human cells also in the absence of viruses. We identify phosphorothioate DNAs (PS DNAs) as triggers of such endogenous dsRNA (endo-dsRNA). PS DNAs inhibit decay of nuclear RNAs and induce endo-dsRNA via accumulation of high levels of intronic and intergenic inverted retroelements (IIIR). IIIRs activate endo-dsRNA responses distinct from antiviral defense programs. IIIRs do not turn on transcriptional RIG-I/MDA5/IFN signaling, but they trigger the dsRNA-sensing pathways of OAS3/RNase L and PKR. Thus, nuclear RNA decay and nuclear-cytosolic RNA sorting actively protect from these innate immune responses to self. Our data suggest that the OAS3/RNase L and PKR arms of innate immunity diverge from antiviral IFN responses and monitor nuclear RNA decay by sensing cytosolic escape of IIIRs. OAS3 provides a receptor for IIIRs, whereas RNase L cleaves IIIR-carrying introns and intergenic RNAs.

scholarly journals A phenolic small molecule inhibitor of RNase L prevents cell death from ADAR1 deficiency

2020 ◽  
Vol 117 (40) ◽  
pp. 24802-24812 ◽  
Author(s):  
Salima Daou ◽  
Manisha Talukdar ◽  
Jinle Tang ◽  
Beihua Dong ◽  
Shuvojit Banerjee ◽  
...  
Keyword(s):  
Cell Death ◽  
Protein Kinase ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Therapeutic Potential ◽  
Protein Kinase Inhibitors ◽  
Response To Treatment ◽  
Rnase L ◽  
Oligoadenylate Synthetase ◽  
In Cells

The oligoadenylate synthetase (OAS)–RNase L system is an IFN-inducible antiviral pathway activated by viral infection. Viral double-stranded (ds) RNA activates OAS isoforms that synthesize the second messenger 2-5A, which binds and activates the pseudokinase-endoribonuclease RNase L. In cells, OAS activation is tamped down by ADAR1, an adenosine deaminase that destabilizes dsRNA. Mutation of ADAR1 is one cause of Aicardi-Goutières syndrome (AGS), an interferonopathy in children. ADAR1 deficiency in human cells can lead to RNase L activation and subsequent cell death. To evaluate RNase L as a possible therapeutic target for AGS, we sought to identify small-molecule inhibitors of RNase L. A 500-compound library of protein kinase inhibitors was screened for modulators of RNase L activity in vitro. We identified ellagic acid (EA) as a hit with 10-fold higher selectivity against RNase L compared with its nearest paralog, IRE1. SAR analysis identified valoneic acid dilactone (VAL) as a superior inhibitor of RNase L, with 100-fold selectivity over IRE1. Mechanism-of-action analysis indicated that EA and VAL do not bind to the pseudokinase domain of RNase L despite acting as ATP competitive inhibitors of the protein kinase CK2. VAL is nontoxic and functional in cells, although with a 1,000-fold decrease in potency, as measured by RNA cleavage activity in response to treatment with dsRNA activator or by rescue of cell lethality resulting from self dsRNA induced by ADAR1 deficiency. These studies lay the foundation for understanding novel modes of regulating RNase L function using small-molecule inhibitors and avenues of therapeutic potential.

The 2-5A/RNase L Pathway and Inhibition by RNase L Inhibitor (RLI)

2003 ◽  
pp. 183-198 ◽  
Author(s):  
Catherine Bisbal ◽  
Tamim Salehzada ◽  
Michelle Silhol ◽  
Camille Martinand ◽  
Florence Le Roy ◽  
...  
Keyword(s):  
Rnase L ◽  
Rnase L Inhibitor
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