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

Konstantinos Stellos, Aikaterini Gatsiou, Kimon Stamatelopoulos, Ljubica Perisic Matic, David John, Federica Francesca Lunella, Nicolas Jaé, Oliver Rossbach, Carolin Amrhein, Frangiska Sigala, Reinier A Boon, Boris Fürtig, Yosif Manavski, Xintian You, Shizuka Uchida, Till Keller, Jes-Niels Boeckel, Anders Franco-Cereceda, Lars Maegdefessel, Wei ChenHarald Schwalbe, Albrecht Bindereif, Per Eriksson, Ulf Hedin, Andreas M Zeiher, Stefanie Dimmeler

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)1140-1150
Number of pages11
JournalNature Medicine
Volume22
Issue number10
DOIs
Publication statusPublished - 2016

Cite this

Stellos, K., Gatsiou, A., Stamatelopoulos, K., Perisic Matic, L., John, D., Lunella, F. F., ... Dimmeler, S. (2016). Adenosine-to-inosine RNA editing controls cathepsin S expression in atherosclerosis by enabling HuR-mediated post-transcriptional regulation. Nature Medicine, 22(10), 1140-1150. https://doi.org/10.1038/nm.4172