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Oxidative stress enhances the expression of 2',3'-cyclic phosphate-containing RNAs.

ABSTRACT: Eukaryotic cells equip robust systems to respond to stress conditions. In stressed mammalian cells, angiogenin endoribonuclease cleaves anticodon-loops of tRNAs to generate tRNA halves termed tRNA-derived stress-induced RNAs (tiRNAs), which promote stress granule formation and regulate translation. The 5'-tiRNAs (5'-tRNA halves) contain a 2',3'-cyclic phosphate (cP) and thus belong to cP-containing RNAs (cP-RNAs). The cP-RNAs form a hidden layer of the transcriptome because standard RNA-seq cannot amplify and sequence them. In this study, we performed genome-wide analyses of short cP-RNA transcriptome in oxidative stress-exposed human cells. Using cP-RNA-seq that can specifically sequence cP-RNAs, we identified tiRNAs and numerous other cP-RNAs that are mainly derived from rRNAs and mRNAs. Although tiRNAs were produced from a wide variety of tRNA species, abundant species of tiRNAs were derived from a focal-specific subset of tRNAs. Regarding rRNA- and mRNA-derived cP-RNAs, determination of the processing sites of substrate RNAs revealed highly specific RNA cleavage events between pyrimidines and adenosine in generation of those cP-RNAs. Those cP-RNAs were derived from specific loci of substrate RNAs rather than from the overall region, implying that cP-RNAs are produced by regulated biogenesis pathways and not by random degradation events. We experimentally confirmed the identified sequences to be expressed as cP-RNAs in the cells, and their expressions were upregulated upon induction of oxidative stress. These analyses of the cP-RNA transcriptome unravel an abundant class of short ncRNAs that accumulate in cells under oxidative stress.

SUBMITTER: Shigematsu M

PROVIDER: S-EPMC7549721 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Interleukin-33 (IL-33) is a cytokine belonging to the IL-1 family, and its possible involvement in the pathophysiology of COPD and viral-induced exacerbations has been demonstrated. IL-33 has been shown to be increased in the airway epithelial cells from COPD patients, but the regulating mechanism of IL-33 expression in airway epithelial cells remains largely unknown. In the current study, we examined whether oxidative stress, which participates in the pathogenesis of COPD, affects the expression of IL-33 in airway epithelial cells and also evaluated the effect during viral infection. METHODS:The involvement of oxidative stress in the expression of IL-33, and its signal pathway was examined after stimulation with hydrogen peroxide (H2O2), with or without stimulation by polyinosinic-polycytidylic acid [poly (I:C)], a synthetic analogue of dsRNA that mimics viral infection, or rhinovirus infection in NCI-H292 cells and primary human bronchial epithelial cells (HBECs). In addition, the effect of antioxidant, N-acetylcysteine (NAC) in the expression of IL-33 was compared between HBECs from healthy subjects and those from COPD patients. RESULTS:Treatment with H2O2 significantly potentiated IL-33 expression in NCI-H292 cells, and the potentiation was reversed by NAC treatment. Mitogen-activated protein kinase (MAPK) inhibitors, but not nuclear factor-kappa B inhibitors, also significantly decreased the H2O2-potentiated IL-33 expression. In addition, H2O2 significantly potentiated the poly (I:C)- or rhinovirus-stimulated IL-33 expression. In HBECs from healthy subjects, H2O2-potentiated IL-33 expression and its reversal by NAC was also confirmed. Under the condition without H2O2-stimulation, treatment with NAC significantly decreased the expression of IL-33 in HBECs from COPD patients, but not in those from healthy subjects. CONCLUSIONS:These results demonstrate that oxidative stress involves in the expression of IL-33 in airway epithelial cells via MAPK signal pathway and it augments IL-33 expression during viral infection. This mechanism may participate in the regulation of IL-33 expression in airway epithelial cells in COPD and the viral-induced exacerbations. Modulation of this pathway could become a therapeutic target for viral-induced exacerbations of COPD.

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Oxidative stress enhances the expression of 2',3'-cyclic phosphate-containing RNAs.

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