scholarly journals Curcumin, a Natural Antioxidant, Acts as a Noncompetitive Inhibitor of Human RNase L in Presence of Its Cofactor 2-5AIn Vitro

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Ankush Gupta ◽  
Pramod C. Rath
Keyword(s):  
Innate Immune System ◽  
Mammalian Cells ◽  
Viral Infections ◽  
Innate Immune ◽  
Therapeutic Interventions ◽  
Active Principle ◽  
Rnase L ◽  
Double Stranded Rna ◽  
Human Rnase ◽  
Noncompetitive Inhibitor

Ribonuclease L (RNase L) is an antiviral endoribonuclease of the innate immune system, which is induced and activated by viral infections, interferons, and double stranded RNA (dsRNA) in mammalian cells. Although, RNase L is generally protective against viral infections, abnormal RNase L expression and activity have been associated with a number of diseases. Here, we show that curcumin, a natural plant-derived anti-inflammatory active principle, inhibits RNase L activity; hence, it may be exploited for therapeutic interventions in case of pathological situations associated with excess activation of RNase L.

scholarly journals Human RNase L tunes gene expression by selectively destabilizing the microRNA-regulated transcriptome

2015 ◽  
Vol 112 (52) ◽  
pp. 15916-15921 ◽  
Author(s):  
Sneha Rath ◽  
Jesse Donovan ◽  
Gena Whitney ◽  
Alisha Chitrakar ◽  
Wei Wang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Innate Immune System ◽  
Mammalian Cells ◽  
Innate Immune ◽  
Rnase L ◽  
Double Stranded Rna ◽  
Rna Targets ◽  
Human Rnase ◽  
Cell Growth And Differentiation ◽  
Cell Adhesion And Proliferation

Double-stranded RNA (dsRNA) activates the innate immune system of mammalian cells and triggers intracellular RNA decay by the pseudokinase and endoribonuclease RNase L. RNase L protects from pathogens and regulates cell growth and differentiation by destabilizing largely unknown mammalian RNA targets. We developed an approach for transcriptome-wide profiling of RNase L activity in human cells and identified hundreds of direct RNA targets and nontargets. We show that this RNase L-dependent decay selectively affects transcripts regulated by microRNA (miR)-17/miR-29/miR-200 and other miRs that function as suppressors of mammalian cell adhesion and proliferation. RNase L mimics the effects of these miRs and acts as a suppressor of proliferation and adhesion in mammalian cells. Our data suggest that RNase L-dependent decay serves to establish an antiproliferative state via destabilization of the miR-regulated transcriptome.

scholarly journals Y-RNA and tRNA Cleavage by RNase L Mediates Terminal dsRNA Response

2016 ◽  
Author(s):  
Jesse Donovan ◽  
Sneha Rath ◽  
David Kolet-Mandrikov ◽  
Alexei Korennykh
Keyword(s):  
Small Rnas ◽  
Mammalian Cells ◽  
Innate Immune ◽  
Rna Cleavage ◽  
Rnase L ◽  
Rna Seq ◽  
Danger Signal ◽  
Double Stranded Rna ◽  
Transfer Rnas ◽  
Non Coding Rna

AbstractDouble-stranded RNA (dsRNA) is a danger signal that triggers endonucleolytic degradation of RNA inside infected and stressed mammalian cells. This mechanism inhibits growth and ultimately removes problematic cells via apoptosis. To elucidate the molecular functions of this program and understand the connection between RNA cleavage and programmed cell death, we visualized dsRNA-induced degradation of human small RNAs using RtcB ligase-assisted RNA sequencing (RtcB RNA-seq). RtcB RNA-seq revealed strong cleavage of select transfer RNAs (tRNAs) and autoantigenic Y-RNAs, and identified the innate immune receptor RNase L as the responsible endoribonuclease. RNase L cleaves the non-coding RNA (ncRNA) targets site-specifically, releasing abundant ncRNA fragments, and downregulating full-length tRNAs and Y-RNAs. The depletion of a single Y-RNA, RNY1, appears particularly important and the loss of this Y-RNA is sufficient to initiate apoptosis. Site-specific cleavage of small ncRNA by RNase L thus emerges as an important terminal step in dsRNA surveillance.

scholarly journals Real-time 2-5A kinetics suggest that interferons β and λ evade global arrest of translation by RNase L

2019 ◽  
Vol 116 (6) ◽  
pp. 2103-2111 ◽  
Author(s):  
Alisha Chitrakar ◽  
Sneha Rath ◽  
Jesse Donovan ◽  
Kaitlin Demarest ◽  
Yize Li ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Innate Immune System ◽  
Innate Immune ◽  
Host Protein ◽  
Rna Cleavage ◽  
Rnase L ◽  
Foreign Material ◽  
Defense Proteins ◽  
Double Stranded Rna ◽  
Host Protein Synthesis

Cells of all mammals recognize double-stranded RNA (dsRNA) as a foreign material. In response, they release interferons (IFNs) and activate a ubiquitously expressed pseudokinase/endoribonuclease RNase L. RNase L executes regulated RNA decay and halts global translation. Here, we developed a biosensor for 2′,5′-oligoadenylate (2-5A), the natural activator of RNase L. Using this biosensor, we found that 2-5A was acutely synthesized by cells in response to dsRNA sensing, which immediately triggered cellular RNA cleavage by RNase L and arrested host protein synthesis. However, translation-arrested cells still transcribed IFN-stimulated genes and secreted IFNs of types I and III (IFN-β and IFN-λ). Our data suggest that IFNs escape from the action of RNase L on translation. We propose that the 2-5A/RNase L pathway serves to rapidly and accurately suppress basal protein synthesis, preserving privileged production of defense proteins of the innate immune system.

scholarly journals Cellular Responses to Cytosolic Double-stranded RNA–-The Role of the Inflammasome

2014 ◽  
Vol 6 ◽  
pp. III.S17839 ◽  
Author(s):  
Adi Idris
Keyword(s):  
Innate Immune System ◽  
Viral Infections ◽  
Cellular Responses ◽  
Specific Pattern ◽  
Innate Immune ◽  
Host Cells ◽  
Virus Infected Cell ◽  
Double Stranded Rna ◽  
Molecular Patterns

Sensing the presence of a pathogen is an evolutionarily ancient trait, especially for cells of the innate immune system. The innate immune response against pathogens, such as viruses, begins with recognition of pathogen-associated molecular patterns (PAMPs) by specific pattern-recognition receptors (PRRs). Cytosolic double-stranded RNA (dsRNA) is emerging as a critical PAMP in the detection of viral infections. This recognition results in the production of antiviral and proinflammatory cytokines and, often, the death of the virus-infected cell. This review focuses on the current developments in the role of inflammasomes in response to the presence of cytosolic dsRNA in host cells. More importantly, it highlights important unanswered questions that if addressed will help us better understand the ways in which host cells respond to viral infection, in particular RNA viruses.

scholarly journals Shapeshifting RNAs guide innate immunity

2018 ◽  
Vol 293 (41) ◽  
pp. 16125-16126 ◽  
Author(s):  
Jonathan D. Dinman
Keyword(s):  
Immune Response ◽  
Pattern Recognition ◽  
Innate Immune System ◽  
Viral Infections ◽  
Innate Immune ◽  
Rnase L ◽  
Cellular Origin ◽  
Wide Range ◽  
Conformational Plasticity ◽  
Recognition Receptor

The innate immune system can distinguish between RNAs of viral and cellular origin, but the basis for this discrimination is not known. A new paper by Calderon and Conn demonstrates that conformational plasticity determines the ability of one RNA sequence to bind to and activate the pattern recognition receptor OAS1/RNase L. In identifying a novel mode through which the immune response is naturally controlled, this finding opens new avenues toward developing approaches for the management of a wide range of viral infections.

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 Therapeutic Interventions into Innate Immune Diseases by Means of Aptamers

Pharmaceutics ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 955
Author(s):  
Farzana Yasmeen ◽  
Hana Seo ◽  
Nasir Javaid ◽  
Moon Suk Kim ◽  
Sangdun Choi
Keyword(s):  
Pattern Recognition ◽  
Immune System ◽  
Crucial Role ◽  
Innate Immune System ◽  
Innate Immune ◽  
Therapeutic Interventions ◽  
Immune System Diseases ◽  
Target Molecules ◽  
Molecular Patterns ◽  
Recognition Receptor

The immune system plays a crucial role in the body’s defense system against various pathogens, such as bacteria, viruses, and parasites, as well as recognizes non-self- and self-molecules. The innate immune system is composed of special receptors known as pattern recognition receptors, which play a crucial role in the identification of pathogen-associated molecular patterns from diverse microorganisms. Any disequilibrium in the activation of a particular pattern recognition receptor leads to various inflammatory, autoimmune, or immunodeficiency diseases. Aptamers are short single-stranded deoxyribonucleic acid or ribonucleic acid molecules, also termed “chemical antibodies,” which have tremendous specificity and affinity for their target molecules. Their features, such as stability, low immunogenicity, ease of manufacturing, and facile screening against a target, make them preferable as therapeutics. Immune-system–targeting aptamers have a great potential as a targeted therapeutic strategy against immune diseases. This review summarizes components of the innate immune system, aptamer production, pharmacokinetic characteristics of aptamers, and aptamers related to innate-immune-system diseases.

scholarly journals Double-Stranded RNA Is Produced by Positive-Strand RNA Viruses and DNA Viruses but Not in Detectable Amounts by Negative-Strand RNA Viruses

2006 ◽  
Vol 80 (10) ◽  
pp. 5059-5064 ◽  
Author(s):  
Friedemann Weber ◽  
Valentina Wagner ◽  
Simon B. Rasmussen ◽  
Rune Hartmann ◽  
Søren R. Paludan
Keyword(s):  
Viral Infections ◽  
Rna Viruses ◽  
Innate Immune ◽  
Genome Replication ◽  
Dna Viruses ◽  
Double Stranded Rna ◽  
Positive Strand ◽  
Negative Strand ◽  
A Genome ◽  
Positive Strand Rna

ABSTRACT Double-stranded RNA (dsRNA) longer than 30 bp is a key activator of the innate immune response against viral infections. It is widely assumed that the generation of dsRNA during genome replication is a trait shared by all viruses. However, to our knowledge, no study exists in which the production of dsRNA by different viruses is systematically investigated. Here, we investigated the presence and localization of dsRNA in cells infected with a range of viruses, employing a dsRNA-specific antibody for immunofluorescence analysis. Our data revealed that, as predicted, significant amounts of dsRNA can be detected for viruses with a genome consisting of positive-strand RNA, dsRNA, or DNA. Surprisingly, however, no dsRNA signals were detected for negative-strand RNA viruses. Thus, dsRNA is indeed a general feature of most virus groups, but negative-strand RNA viruses appear to be an exception to that rule.

scholarly journals SARS-CoV-2 induces double-stranded RNA-mediated innate immune responses in respiratory epithelial-derived cells and cardiomyocytes

2021 ◽  
Vol 118 (16) ◽  
pp. e2022643118
Author(s):  
Yize Li ◽  
David M. Renner ◽  
Courtney E. Comar ◽  
Jillian N. Whelan ◽  
Hanako M. Reyes ◽  
...  
Keyword(s):  
Induced Pluripotent Stem Cell ◽  
Cell Types ◽  
Innate Immune ◽  
Alveolar Type ◽  
Rnase L ◽  
Oligoadenylate Synthetase ◽  
Protein Kinase R ◽  
Double Stranded Rna ◽  
Induced Pluripotent ◽  
Host Virus Interactions

Coronaviruses are adept at evading host antiviral pathways induced by viral double-stranded RNA, including interferon (IFN) signaling, oligoadenylate synthetase–ribonuclease L (OAS-RNase L), and protein kinase R (PKR). While dysregulated or inadequate IFN responses have been associated with severe coronavirus infection, the extent to which the recently emerged SARS-CoV-2 activates or antagonizes these pathways is relatively unknown. We found that SARS-CoV-2 infects patient-derived nasal epithelial cells, present at the initial site of infection; induced pluripotent stem cell-derived alveolar type 2 cells (iAT2), the major cell type infected in the lung; and cardiomyocytes (iCM), consistent with cardiovascular consequences of COVID-19 disease. Robust activation of IFN or OAS-RNase L is not observed in these cell types, whereas PKR activation is evident in iAT2 and iCM. In SARS-CoV-2–infected Calu-3 and A549ACE2 lung-derived cell lines, IFN induction remains relatively weak; however, activation of OAS-RNase L and PKR is observed. This is in contrast to Middle East respiratory syndrome (MERS)-CoV, which effectively inhibits IFN signaling and OAS-RNase L and PKR pathways, but is similar to mutant MERS-CoV lacking innate immune antagonists. Remarkably, OAS-RNase L and PKR are activated in MAVS knockout A549ACE2 cells, demonstrating that SARS-CoV-2 can induce these host antiviral pathways despite minimal IFN production. Moreover, increased replication and cytopathic effect in RNASEL knockout A549ACE2 cells implicates OAS-RNase L in restricting SARS-CoV-2. Finally, while SARS-CoV-2 fails to antagonize these host defense pathways, which contrasts with other coronaviruses, the IFN signaling response is generally weak. These host–virus interactions may contribute to the unique pathogenesis of SARS-CoV-2.

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