Structure and degradation of circular RNAs regulate PKR activation in innate immunity
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA507020 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8245150_1.fastq.gz | Fastqsanger.gz | |||
| SRR8245150_2.fastq.gz | Fastqsanger.gz | |||
| SRR8245160_1.fastq.gz | Fastqsanger.gz | |||
| SRR8245160_2.fastq.gz | Fastqsanger.gz | |||
| SRR8245151_1.fastq.gz | Fastqsanger.gz |
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Project description:Exon(s) back-splicing-generated circular RNAs as a group can suppress the double-stranded RNA (dsRNA)-activated protein kinase R (PKR) in cells. We have sought to synthesize immunogenicity-free, short dsRNA-containing circular RNAs as potent PKR inhibitors. Here, we report that circular RNAs synthesized by permuted td introns from T4 bacteriophage and by Anabeana pre-tRNA group I intron induce an immune response. Mechanistically, autocatalytic splicing introduces extra ~74 nt and ~186 nt fragments (E1+E2+spacer) that form additional stable loop structures that likely provoke innate immune responses in circular RNA products. In contrast, circular RNAs produced by T4 RNA ligase without unwanted fragment exhibit little immunogenicity. Importantly, directly-ligated circular RNAs form short dsRNA-regions exhibit 103~106 fold higher efficiency than the reported chemical compounds C16 and 2-AP in suppressing PKR activation, highlighting the use of circular RNAs as novel inhibitors for PKR over-reaction diseases.
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Project description:Efforts to advance RNA aptamers as a novel therapeutic modality have been limited by their susceptibilty to degradation and immunogenicity. In a previous study, we demonstrated synthesized double-stranded circular RNAs (ds-cRNAs) with minimal immunogenicity targeted to dsRNA-activated Protein Kinase R (PKR). Here, we test the therapeutic potential of ds-cRNAs in a mouse model of imiquimod-induced psoriasis. We find that genetic supplementation of ds-cRNAs leads to inhibition of PKR, resulting in alleviation of downstream interferon alpha (IFNα)/dsRNA signals and attenuation of psoriasis phenotypes. Delivery of ds-cRNAs by lipid nanoparticles to the spleen attenuates PKR activity in examined splenocytes, resulting in reduced epidermal thickness. These findings suggest that ds-cRNAs represent a promising approach to mitigate excessive PKR activation for therapeutic purposes.
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Project description:Protein kinase R (PKR), an innate immune sensor for double-stranded RNA (dsRNA), is critical for antiviral defense, but its aberrant activation by cellular dsRNA is linked to various diseases. The dsRNA-binding protein PACT plays a crucial and controversial role in the PKR pathway. We demonstrate that PACT is an essential negative regulator of PKR against endogenous dsRNA ligands like inverted repeat Alu RNAs, which satisfy PKR’s selectivity for long dsRNA and robustly activate PKR in the absence of PACT. PACT employs an unusual inhibitory mechanism sensitive to dsRNA length and concentration, inhibiting PKR through low-affinity interactions most effective when both are bound to the same dsRNA molecule. Consequently, PACT’s inhibition of PKR is more robust when dsRNA is longer and less abundant, with minimal effect on abundant or short dsRNA. Thus, PACT functions as a rheostat, setting the PKR activation threshold for long endogenous dsRNA without altering its inherent activity.
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Project description:Circular RNAs (circRNAs) have emerged as a new type of endogenous non-coding RNA characterized by their covalently closed circular structure and a backspliced junction (BSJ) resulting from a back-splicing process. In the last years, several studies have shown that circRNAs are important modulators in the immune system, activation of inflammation, antibacterial and antiviral responses as well as autoimmune diseases, such as multiple sclerosis. In the last years, it has been proposed that a subset of circRNA form imperfect double-stranded structures that allow them to interact with PKR (double stranded RNA-activated protein kinase), an intracellular protein responsible for recognizing long double stranded RNAs, usually viral RNAs, in the cytoplasm and trigger an anti-viral response of the cell. Taking into account the implication of the innate immune response in multiple sclerosis pathophysiology and the discovery of circRNA deregulation in multiple sclerosis patients, we wanted to investigate the circRNA-PKR crosstalk and its implication in the pathology of multiple sclerosis. Using an in vitro model of the anti-viral response and RNA-seq to characterize circRNA expression, we observed that poly (I:C) (a double-stranded RNA) stimulation produces a global downregulation of circRNA, PKR phosphorylation and immune-related gene activation and that these effects are reversed when treatment is stopped. Additionally, we found that the overexpression of double stranded RNA-containing circRNAs is able to reduce the PKR phosphorylation and the activation of immune-related pathways induced by poly(I:C). Finally, we measured the PKR phosphorylation in PBMCs isolated from multiple sclerosis patients in relapse and remission phases, but we did not obtain conclusive results since there is a very big variability between samples. In conclusion, this work reinforces the evidence on the mechanism describing the interaction between PKR and circRNA containing double-stranded structures and their role in the immune response. Besides, our experiments highlight the importance of the structure in circRNA function. Lastly, it also sheds some light into the possible implication of the circRNA-PKR axis in multiple sclerosis although further research is needed to make a better characterization of this mechanism in order to understand its potential role in the regulation of the immune response of the disease.
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Project description:PKR (Protein Kinase RNA-activated) is activated by metabolic stress, such as that associated with obesity, and this activation depends on its RNA-binding domain. Here we investigated whether endogenous RNA triggers PKR activation in response to lipid exposure. Our results indicate that snoRNAs (small nucleolar RNAs) associate with PKR during metabolic stress. Our high-throughput sequence shows that snoRNAs are enriched in PKR_WT samples after palmitic acid treatment compared to mock-treated samples. MEF cells reconstituted with wild type PKR (PKR_WT) or PKR with a mutation in each dsRBM (PKR_RM) were mock- or palmitate-treated. RNAs associated with PKR were immunoprecipitated. IPed RNAs were extracted, cloned and sequenced. We performed differential expression to obtain RNAs enriched in PKRWT after palmitate treatment. We sequenced three different datasets of samples (A, B and C). Each A and B dataset contains three biological replicates. Dataset C contains a single sample.
2015-05-08 | E-GEOD-66540 | biostudies-arrayexpress
Project description:Global analysis of gene expression in NIH3T3 cells over-expressing RNA-dependent serine/threonine protein kinase (PKR).
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Project description:The Circular RNA Edis Regulates Neurodevelopment and Innate Immunity
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Project description:Circular RNAs (circRNAs) are widely expressed in eukaryotes. However, only a subset have been functionally characterized. We identify and validate a collection of circRNAs in Drosophila, and show that depletion of the brain-enriched circRNA Edis causes hyperactivation of antibacterial innate immunity both in cultured cells and in vivo. Notably, Edis depleted flies display heightened resistance to bacterial infection and enhanced pathogen clearance. Conversely, ectopic Edis expression blocks innate immunity signaling. In addition, inactivation of Edis in vivo leads to impaired locomotive activity and shortened lifespan. Remarkably, these phenotypes can be recapitulated with neuron-specific depletion of Edis, accompanied by defective neurodevelopment. Importantly, restoration of Edis expression suppresses both innate immunity and neurodevelopment phenotypes elicited by Edis depletion. We provide evidence that Edis encodes a functional protein that associates with and compromises the processing of the immune transcription factor Relish. Consistent with these observations, inactivation of Relish suppresses the innate immunity hyperactivation phenotype in the fly brain and rescues the neurodevelopment defects in Edis knockdown neurons. Thus, our study establishes the circRNA Edis as a key regulator of neurodevelopment and innate immunity.
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