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New role of RNA editing in vascular disease

September 2016. Enzymes of the ADAR family bind to double-stranded RNAs and catalyze the deamination of the nucleoside adenosine to inosine (A-to-I). This process, called RNA editing, is a ubiquitous and crucial post-transcriptional modification of genome-encoded RNA transcripts. A team of scientists has shown that cathepsin S (CTSS) mRNA, 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, which reveal a previously unrecognized role of RNA editing in gene expression in human atherosclerotic vascular diseases, were published recently in the journal Nature Medicine. More...

Stefanie Dimmeler
Institute of Cardiovascular Regeneration
Goethe-University Frankfurt

Full reference:
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 JN, Franco-Cereceda A, Maegdefessel L, Chen W, Schwalbe H, Bindereif A, Eriksson P, Hedin U, Zeiher AM, Dimmeler S (2016) Adenosine-to-inosine RNA editing controls cathepsin S expression in atherosclerosis by enabling HuR-mediated post-transcriptional regulation. Nature Medicine, published online 5 September 2016, http://dx.doi.org/10.1038/nm.4172