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

Official URL:https://doi.org/10.1038/nm.4172
PubMed:View item in PubMed
Creators Name:Stellos, K. and Gatsiou, A. and Stamatelopoulos, K. and Perisic Matic, L. and John, D. and Lunella, F.F. and Jae, N. and Rossbach, O. and Amrhein, C. and Sigala, F. and Boon, R.A. and Fuertig, B. and Manavski, Y. and You, X. and Uchida, S. and Keller, T. and Boeckel, J.N. and Franco-Cereceda, A. and Maegdefessel, L. and Chen, W. and Schwalbe, H. and Bindereif, A. and Eriksson, P. and Hedin, U. and Zeiher, A.M. and Dimmeler, S.
Journal Title:Nature Medicine
Journal Abbreviation:Nat Med
Volume:22
Number:10
Page Range:1140-1150
Date:October 2016
Keywords:3' Untranslated Regions, Adenosine, Adenosine Deaminase, Aortic Aneurysm, Atherosclerosis, Carotid Artery Diseases, Cathepsins, Coronary Artery Disease, ELAV-Like Protein 1, Fluorescent Antibody Technique, Gene Expression Regulation, Gene Knock-In Techniques, Gene Knockdown Techniques, High-Throughput Nucleotide Sequencing, Human Umbilical Vein Endothelial Cells, Hypoxia, Immunoblotting, Inosine, Interferon-gamma, Messenger RNA, Post-Transcriptional RNA Processing, RNA Editing, RNA Sequence Analysis, RNA-Binding Proteins, Real-Time Polymerase Chain Reaction, Tumor Necrosis Factor-alpha
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-{gamma} and tumor-necrosis-factor-{alpha} 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.
ISSN:1078-8956
Publisher:Nature Publishing Group (U.S.A.)
Item Type:Article

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