Dom34 mediates targeting of exogenous RNA in the antiviral OAS/RNase L pathway

Nishiura, Kyutatsu; Kawashima, Sho; Nagai, Takahiro; Oishi, Yuka; Hosoda, Naoe; Imataka, Hiroaki; Kitamura, Yoshiaki; Kitade, Yukio; Hoshino, Shin‐ichi

doi:10.1093/nar/gky1087

Cited by 32 publications

(39 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although it remains to be explained precisely how live cells achieve Briggs-Haldane regime, our observations could be explained by ribosomeassisted RNase L access to mRNAs. This model agrees with the recently proposed mechanism for Dom34 rescue of RNase L-ribosome complex, which postulates a translation-dependent mRNA cleavage mechanism (Nogimori et al, 2018). If ribosome-RNase L recognition (rather than mRNA-RNase L recognition) determines kinetics mRNA decay by RNase L, 2-5AMD would target all actively translating mRNAs.…”

Section: Discussionsupporting

confidence: 88%

“…6A), suggesting that translation could render mRNAs more sensitive to RNase L compared to ncRNAs. The potential dependence on translation appears to be in line with the recently proposed model for translation-dependent RNase L cleavage based on analysis of decay of exogenous RNA (Nogimori et al, 2018).…”

Section: Decay and Synthesis Kinetics Protect Ifn Mrnas From 2-5amdsupporting

confidence: 82%

“…However, even the most sensitive tRNAs were intact at the time of translational inhibition, suggesting that the only RNA substrates that could account for the translational inhibition are mRNAs. RNase L has been shown to cleave exogenous mRNAs, viral mRNAs and select host mRNAs with a preference for longer RNAs with many AU-rich elements due to the specificity of RNase L for UN^N sites (Al-Ahmadi et al, 2009;Le Roy et al, 2007;Nogimori et al, 2018;. To produce the uniform loss of global translation by mRNA decay, 2-5AMD must act similarly on all housekeeping mRNAs.…”

Section: Spike-in Poly-a + Rna-seq Reveals Global Decay Of Messenger mentioning

confidence: 99%

See 2 more Smart Citations

Concerted 2-5A-Mediated mRNA Decay and Transcription Reprogram Protein Synthesis in dsRNA Response

Rath

Prangley

Donovan

et al. 2018

Preprint

View full text Add to dashboard Cite

RNA degradation by RNase L during 2-5A-mediated decay (2-5AMD) is a conserved mammalian stress response to viral and endogenous double-stranded RNA (dsRNA). 2-5AMD onsets rapidly and facilitates a switch of protein synthesis from homeostasis to production of interferons (IFNs). To understand the mechanism of this protein synthesis reprogramming, we examined 2-5AMD in human cells. 2-5AMD triggers polysome collapse characteristic of a translation initiation defect, but translation initiation complexes and ribosomes purified from the translation-arrested cells remain functional. Using spike-in RNA-seq we found that basal messenger RNAs (mRNAs) rapidly decay, while mRNAs encoding IFNs and IFN-stimulated genes evade 2-5AMD and accumulate. The IFN evasion results from the combined effect of better mRNA stability and positive feedback amplification in the IFN response. Therefore, 2-5AMD and transcription act in concert to revamp the cellular mRNA composition. The resulting preferential accumulation of innate immune mRNAs establishes "prioritized" synthesis of defense proteins.

show abstract

Section: Discussionsupporting

confidence: 88%

Section: Decay and Synthesis Kinetics Protect Ifn Mrnas From 2-5amdsupporting

confidence: 82%

Section: Spike-in Poly-a + Rna-seq Reveals Global Decay Of Messenger mentioning

confidence: 99%

See 1 more Smart Citation

Concerted 2-5A-Mediated mRNA Decay and Transcription Reprogram Protein Synthesis in dsRNA Response

Rath

Prangley

Donovan

et al. 2018

Preprint

View full text Add to dashboard Cite

show abstract

“…In our investigation on Protein kinase R (PKR) pathway to see if EIF2A inhibits the translation of mRNA, we detected elevated expressions of EIF2A by unmodified mRNA and control R848 . Later, we wanted to identify if expressions of previously mentioned signaling molecules were interrelated to RNA degradation by the 2′‐5′‐oligoadenylate synthetase (OAS)/RNase L pathway . Here, we noticed that the RNASEL were expressed relatively higher in unmodified mRNA treated sample compared to modified version.…”

Section: Discussionmentioning

confidence: 95%

RNA ImmunoGenic Assay: Simple method for detecting immunogenicity of in vitro transcribed mRNA

et al. 2020

View full text Add to dashboard Cite

In vitro transcribed (IVT) mRNA therapies is a promising approach for the effective and safe treatment of various diseases. However, IVT‐mRNA triggers immune responses due to recognition by human RNA sensors, but incorporation of chemically modified nucleosides have been shown to reduce such responses. Nonetheless, an assay reflecting the complexity of the human immune system is still needed. Here, we present a simple and fast ex vivo method called “RNA Immunogenic Assay” for measuring the immunogenicity of IVT‐mRNA in human whole blood. Chemically modified and unmodified mRNA were complexed with a transfection reagent (TransIT), and co‐incubated in human whole blood and specific cytokines were quantified (TNF‐α, INF‐α, IL‐6, and IL‐12p70) using ELISAs. The qPCR analysis was conducted to unveil the activation of specific immune pathway. Our findings demonstrated that the complete replacement of uridine with pseudouridine reduced TNF‐α, IL‐6, and IL‐12p70 levels and did not elevate the expression of genes involved in immune response against RNA including IRF7/3, EIF2A, & RNASEL. In addition, we observed that the transcript length was not found to be a confounding factor in RNA immunogenicity generation and our assay provide the feasibility to dissect donor specific immune response against mRNA therapeutics.

show abstract

“…exogenous RNA from either virus or bacteria, [21][22][23][24] suggesting that the OAS/RNaseL pathway is a major antiviral defense mechanism. [21][22][23][24][25] Recent research revealed that OAS3 could activate RNase L and inhibited ZIKA virus replication. 26 Therefore, OAS3 mutation enhances the host's susceptibility to viral or bacterial infection, which in turn, activates their inflammation.…”

Section: Discussionmentioning

confidence: 99%

Exome Sequencing Reveals a Heterozygous OAS3 Mutation in a Chinese Family With Juvenile-Onset Open-Angle Glaucoma

Xiao

Huang

Cao

et al. 2019

Invest. Ophthalmol. Vis. Sci.

View full text Add to dashboard Cite

Citation: Xiao X, Huang C, Cao Y, et al. Exome sequencing reveals a heterozygous OAS3 mutation in a Chinese family with juvenile-onset open-angle glaucoma. Invest Ophthalmol Vis Sci. 2019;60:4277-4284. https://doi.org/ 10.1167/iovs.19-27545 PURPOSE.Juvenile-onset open-angle glaucoma (JOAG), if left untreated, will lead to severe visual disability. The purpose of this study was to identify the disease-causing mutations in a Chinese JOAG family. METHODS.We recruited a Chinese JOAG family and unrelated primary open-angle glaucoma (POAG) patients (270, Chinese), and performed whole-exome sequencing (WES) to screen the sequence variations. Variants identified by WES were validated by Sanger sequencing. Subsequently, qPCR and Western blotting were used to determine the expression of wild-type (WT) and its mutated-type (MT) of 2 0 -5 0 -oligoadenylate synthetase 3 (OAS3) genes. RESULTS.Seventeen heterozygous candidate variants were revealed in the JOAG family based on the screening of WES data. Of those, the heterozygous variant exon11:c.2299C>T: p.Arg767Cys in OAS3, a gene used to synthesize 2 0 -5 0 -oligoadenylate (2-5A), co-segregates with the disease phenotype. One unrelated POAG patient also carried this variant, but this variant was absent in 200 nonglaucoma healthy controls. Analysis of the Arg767Cys mutation with PolyPhen2, CADD, and SIFT all suggest that it is pathogenic. This arginine residue is highly conserved in all selected OAS3 orthologs. On the other hand, in peripheral blood samples, the mRNA expression of OAS3 in patients significantly decreased compared with unaffected controls. Moreover, the expression level of recombinant OAS3 protein (mutated Arg767Cys) also observably reduced compared with level of WT protein in HEK293T cells. CONCLUSIONS.Our study revealed a heterozygous mutation in OAS3 from a Chinese JOAG family. And this mutation showed a deleterious effect to the expression of OAS3.

show abstract

Dom34 mediates targeting of exogenous RNA in the antiviral OAS/RNase L pathway

Cited by 32 publications

References 54 publications

Concerted 2-5A-Mediated mRNA Decay and Transcription Reprogram Protein Synthesis in dsRNA Response

Concerted 2-5A-Mediated mRNA Decay and Transcription Reprogram Protein Synthesis in dsRNA Response

RNA ImmunoGenic Assay: Simple method for detecting immunogenicity of in vitro transcribed mRNA

Exome Sequencing Reveals a Heterozygous OAS3 Mutation in a Chinese Family With Juvenile-Onset Open-Angle Glaucoma

Contact Info

Product

Resources

About