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

• Published in: Nature medicine Vol. 22; no. 10; pp. 1140 - 1150
• Main Authors: Stellos, Konstantinos, Gatsiou, Aikaterini, Stamatelopoulos, Kimon, Perisic Matic, Ljubica, John, David, Lunella, Federica Francesca, Jaé, Nicolas, Rossbach, Oliver, Amrhein, Carolin, Sigala, Frangiska, Boon, Reinier A, Fürtig, Boris, Manavski, Yosif, You, Xintian, Uchida, Shizuka, Keller, Till, Boeckel, Jes-Niels, Franco-Cereceda, Anders, Maegdefessel, Lars, Chen, Wei, Schwalbe, Harald, Bindereif, Albrecht, Eriksson, Per, Hedin, Ulf, Zeiher, Andreas M, Dimmeler, Stefanie
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.10.2016; Nature Publishing Group
• Subjects: 13; 13/1; 13/109; 13/21; 13/44; 13/51; 13/89; 13/95; 14/1; 14/19; 3' Untranslated Regions; 38/1; 38/109; 38/70; 38/89; 38/90; 38/91; 42/109; 42/70; 42/89; 45/44; 45/77; 45/90; 45/91; 631/337/1645/1944; 631/80/304; 692/699/75/593/2100; 82/1; 82/51; 96/1; 96/63; Adenosine; Adenosine - metabolism; Adenosine deaminase; Adenosine Deaminase - genetics; Adult; Aged; Aged, 80 and over; Angiogenesis; Aortic Aneurysm - genetics; Arteriosclerosis; Atherosclerosis; Atherosclerosis - genetics; Biomedicine; Cancer Research; Cardiovascular disease; Carotid Artery Diseases - genetics; Cathepsin S; Cathepsins - genetics; Control; Control stability; Coronary artery; Coronary artery disease; Coronary Artery Disease - genetics; Cysteine proteinase; Cytokines; Dosage and administration; Drug therapy; Editing; ELAV-Like Protein 1 - genetics; Endothelial cells; Female; Fluorescent Antibody Technique; Gene expression; Gene Expression Regulation; Gene Knock-In Techniques; Gene Knockdown Techniques; Gene regulation; Genetic aspects; Heart diseases; High-Throughput Nucleotide Sequencing; Human Umbilical Vein Endothelial Cells; Humans; HuR protein; Hypoxia; Hypoxia - genetics; Immunoblotting; Infectious Diseases; Inflammation; Inosine - metabolism; Interferon; Interferon-gamma - pharmacology; Male; Medicin och hälsovetenskap; Metabolic Diseases; Metabolism; Middle Aged; Molecular Medicine; mRNA stability; Neurosciences; Post-transcription; Proteins; Real-Time Polymerase Chain Reaction; Ribonucleic acid; RNA; RNA editing; RNA Editing - drug effects; RNA Editing - genetics; RNA Processing, Post-Transcriptional - drug effects; RNA Processing, Post-Transcriptional - genetics; RNA, Messenger - metabolism; RNA-binding protein; RNA-Binding Proteins - genetics; Sequence Analysis, RNA; Substrates; Tumor Necrosis Factor-alpha - pharmacology; Vascular diseases
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/nm.4172

RNA editing by the adenosine deaminase ADAR1 controls cathepsin S expression in endothelial cells, a mechanism that is implicated in determining cathepsin S levels in patients with atherosclerotic vascular diseases. 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.