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

Stellos, Konstantinos and Gatsiou, Aikaterini and Stamatelopoulos, Kimon and Perisic Matic, Ljubica and John, David and Lunella, Federica Francesca and Jaé, Nicolas and Rossbach, Oliver and Amrhein, Carolin and Sigala, Frangiska and Boon, Reinier A and Fürtig, Boris and Manavski, Yosif and You, Xintian and Uchida, Shizuka and Keller, Till and Boeckel, Jes-Niels and Franco-Cereceda, Anders and Maegdefessel, Lars and Chen, Wei and Schwalbe, Harald and Bindereif, Albrecht and Eriksson, Per and Hedin, Ulf and Zeiher, Andreas M and Dimmeler, Stefanie (2016) Adenosine-to-inosine RNA editing controls cathepsin S expression in atherosclerosis by enabling HuR-mediated post-transcriptional regulation. Nature Medicine, 22 (10). pp. 1140-1150. ISSN 1078-8956

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.