Τίτλος:
Adenosine-to-inosine RNA editing controls cathepsin S expression in atherosclerosis by enabling HuR-mediated post-transcriptional regulation
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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. © 2016 Nature America, Inc. All rights reserved.
Συγγραφείς:
Stellos, K.
Gatsiou, A.
Stamatelopoulos, K.
Perisic Matic, L.
John, D.
Lunella, F.F.
Jaé, N.
Rossbach, O.
Amrhein, C.
Sigala, F.
Boon, R.A.
Fürtig, 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, A.M.
Dimmeler, S.
Περιοδικό:
Journal of Natural Medicines
Εκδότης:
Nature Publishing Group
Λέξεις-κλειδιά:
adenosine; antigen; cathepsin S; ELAV like protein 1; gamma interferon; human antigen R; inosine; messenger RNA; RNA binding protein; tumor necrosis factor; unclassified drug; 3' untranslated region; ADAR1 protein, human; adenosine; adenosine deaminase; cathepsin; cathepsin S; ELAVL1 protein, human; gamma interferon; inosine; tumor necrosis factor, 3' untranslated region; angiogenesis; aorta aneurysm; Article; atherosclerosis; carotid atherosclerosis; controlled study; coronary artery disease; endothelium cell; gene expression; human; human cell; hypoxia; inverted repeat; nucleotide sequence; priority journal; protein expression; RNA editing; RNA stability; adult; aged; aortic aneurysm; atherosclerosis; carotid artery disease; drug effects; female; fluorescent antibody technique; gene expression regulation; gene silencing; gene targeting; genetics; high throughput sequencing; immunoblotting; male; metabolism; middle aged; real time polymerase chain reaction; RNA editing; RNA processing; sequence analysis; umbilical vein endothelial cell; very elderly, 3' Untranslated Regions; Adenosine; Adenosine Deaminase; Adult; Aged; Aged, 80 and over; Aortic Aneurysm; Atherosclerosis; Carotid Artery Diseases; Cathepsins; Coronary Artery Disease; ELAV-Like Protein 1; Female; Fluorescent Antibody Technique; Gene Expression Regulation; Gene Knock-In Techniques; Gene Knockdown Techniques; High-Throughput Nucleotide Sequencing; Human Umbilical Vein Endothelial Cells; Humans; Hypoxia; Immunoblotting; Inosine; Interferon-gamma; Male; Middle Aged; Real-Time Polymerase Chain Reaction; RNA Editing; RNA Processing, Post-Transcriptional; RNA, Messenger; RNA-Binding Proteins; Sequence Analysis, RNA; Tumor Necrosis Factor-alpha
