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

Lookup NU author(s): Professor Konstantinos Stellos

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Abstract

© 2016 Nature America, Inc. All rights reserved. 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-γ 3 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.


Publication metadata

Author(s): Stellos K, Gatsiou A, Stamatelopoulos K, Perisic Matic L, John D, Lunella FF, Jae N, Rossbach O, Amrhein C, Sigala F, Boon RA, Furtig B, Manavski Y, You X, Uchida S, Keller T, Boeckel J-N, Franco-Cereceda A, Maegdefessel L, Chen W, Schwalbe H, Bindereif A, Eriksson P, Hedin U, Zeiher AM, Dimmeler S

Publication type: Article

Publication status: Published

Journal: Nature Medicine

Year: 2016

Volume: 22

Issue: 10

Pages: 1140-1150

Online publication date: 05/09/2016

Acceptance date: 20/07/2016

ISSN (print): 1078-8956

ISSN (electronic): 1546-170X

Publisher: Nature Publishing Group

URL: https://doi.org/10.1038/nm.4172

DOI: 10.1038/nm.4172

PubMed id: 27595325


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