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Nat Med. 2016 Oct;22(10):1140-1150. doi: 10.1038/nm.4172. Epub 2016 Sep 5.

Adenosine-to-inosine RNA editing controls cathepsin S expression in atherosclerosis by enabling HuR-mediated post-transcriptional regulation.

Author information

1
Institute of Cardiovascular Regeneration, Center of Molecular Medicine, Goethe University Frankfurt, Frankfurt, Germany.
2
Department of Cardiology, Center of Internal Medicine, Goethe University Frankfurt, Frankfurt, Germany.
3
German Center of Cardiovascular Research (Deutsches Zentrum für Herz-Kreislaufforschung; DZHK), Rhein-Main Partner Site, Frankfurt, Germany.
4
Department of Clinical Therapeutics, Alexandra Hospital, National and Kapodistrian University of Athens, Athens, Greece.
5
Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.
6
Institute of Biochemistry, University of Giessen, Giessen, Germany.
7
Department of Vascular Surgery, 1st Propaedeutic Department of Surgery, Hippocratio General Hospital, National and Kapodistrian University of Athens, Athens, Greece.
8
Institute for Organic Chemistry and Chemical Biology, Center for Biomolecular Magnetic Resonance, Goethe University Frankfurt, Frankfurt, Germany.
9
Laboratory of Functional Genomics and Systems Biology, Max Delbrück Center for Molecular Medicine Berlin-Buch, Berlin, Germany.
10
Cardiothoracic Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.
11
Cardiovascular Medicine Unit, Department of Medicine, Karolinska Institute, Stockholm, Sweden.
12
Department of Vascular and Endovascular Surgery, Technical University Munich, Munich, Germany.

Abstract

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 3' untranslated region (3' UTR) of the CTSS transcript contains two inverted repeats, the AluJo and AluSx+ regions, which form a long stem-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 3' 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-γ and tumor-necrosis-factor-α 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.

PMID:
27595325
DOI:
10.1038/nm.4172
[Indexed for MEDLINE]

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