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ADAR1 Regulates SFTSV Replication by Modulating miRNA Expression

ABSTRACT: RNA modification plays a crucial role in the regulation of various diseases and viral infections. ADAR1 (adenosine deaminase 1) is a key RNA editing enzyme that can convert adenosine (A) into the modified base inosine (I). This RNA modification has been confirmed to regulate the biological processes of various diseases and viruses. In our previous study on patients with thrombocytopenia syndrome, we conducted a longitudinal sampling study of transcriptomics and epigenetics (Nat. Commun., 2021, 12:5629). In this study, through the analysis of patient RNA-seq, we found that in patients infected with SFTSV, the expression of ADAR1 increased, and it gradually decreased with the recovery of the patients. By constructing cell models and conducting RNA sequencing analysis, we also obtained results similar to those from clinical samples. We found that ADAR1 knockdown promoted the replication of Bunyavirus (SFTSV), while overexpression inhibited virus replication. Further miRNA sequencing analysis revealed that after ADAR1 knockdown, some miRNAs with differential expression were produced, and the target genes of these differentially expressed miRNAs were closely related to neutrophil-mediated immune signaling pathways. These differentially expressed miRNAs may be due to ADAR1 editing the adenosine (A) in the double-stranded region of miRNA precursors to inosine (I), thereby changing the structure of dsRNA and making it difficult for Drosha or Dicer to obtain, thereby reducing the production of miRNAs. Considering these phenomena, we speculate that in the ADAR1 knockdown state, the changes in miRNA expression levels lead to the downregulation of genes involved in neutrophil-mediated immune signaling pathways, potentially causing neutrophil-mediated immune function impairment, thereby enhancing SFTSV replication. These findings provide new insights into the role of ADAR1 in SFTSV replication and immune signaling pathways, and provide a theoretical basis for the development of treatment strategies targeting ADAR1.

ORGANISM(S): Homo sapiens

PROVIDER: GSE286388 | GEO | 2026/01/07

REPOSITORIES: GEO

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Project description:Adenosine-to-inosine (A-to-I) RNA editing, which is catalyzed by a family of adenosine deaminase acting on RNA (ADAR) enzymes, is important in the epitranscriptomic regulation of RNA metabolism. However, the role of A-to-I RNA editing in vascular disease is unknown. Here we show that cathepsin S mRNA (CTSS), which encodes a cysteine protease associated with angiogenesis and atherosclerosis, is highly edited in human endothelial cells. The 3â?² untranslated region (3â?² UTR) of the CTSS transcript contains two inverted repeats, the AluJo and AluSx+ regions, which form a long stemâ??loop structure that is recognized by ADAR1 as a substrate for editing. RNA editing enables the recruitment of the stabilizing RNA-binding protein human antigen R (HuR; encoded by ELAVL1) to the 3â?² UTR of the CTSS transcript, thereby controlling CTSS mRNA stability and expression. In endothelial cells, ADAR1 overexpression or treatment of cells with hypoxia or with the inflammatory cytokines interferon-Î³ and tumor-necrosis-factor-Î± induces CTSS RNA editing and consequently increases cathepsin S expression. ADAR1 levels and the extent of CTSS RNA editing are associated with changes in cathepsin S levels in patients with atherosclerotic vascular diseases, including subclinical atherosclerosis, coronary artery disease, aortic aneurysms and advanced carotid atherosclerotic disease. These results reveal a previously unrecognized role of RNA editing in gene expression in human atherosclerotic vascular diseases. 1) Evaluation of transcriptome expression and RNA editing sites (A-to-G and T-to-C nucleotide mismatches) in poly(A) RNA-seq data derived from endothelial cell transcriptome after ADAR1 or ADAR2 knockdown (n=2 biological replicates per condition, total n=8 biological samples). 2) Evaluation of transcriptome expression and RNA editing sites (A-to-G and T-to-C nucleotide mismatches) in total-RNA-seq data derived from peripheral blood mononuclear cells (n=12 total biological samples; n=4 replicates per condition). 3) Evaluation of transcriptome expression and RNA editing sites (A-to-G and T-to-C nucleotide mismatches) in total-RNA-seq data derived from endothelial cell transcriptome under basal and hypoxic conditions (n=2 biological replicates per condition, total n=4 biological samples). 4) Evaluation of RNA editing sites (A-to-G and T-to-C nucleotide mismatches) in total RNA-seq data derived from endothelial cell transcriptome under basal and hypoxic conditions after ADAR1 knockdown (n=3 replicates per condition, total n=12 biological samples). 5) HuR iCLIP RNA-sequencing data derived from HUVEC HuR iCLIP after ADAR1 knockdown (scrambled control and siADAR1, n=1 per condition, total n=2 biological samples).

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ADAR1 Regulates SFTSV Replication by Modulating miRNA Expression

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