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

Nature Medicine volume 22, pages 1140–1150 (2016)Cite this article

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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.

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Figure 1: ADAR1 controls endothelial cell function and induces widespread A-to-I RNA editing in the transcriptome.
Figure 2: ADAR1-induced CTSS Alu element A-to-I RNA editing controls cathepsin S expression and regulates endothelial cell function.
Figure 3: CTSS mRNA stability is controlled by ADAR1- and RNA-editing-dependent HuR recruitment.
Figure 4: ADAR1 expression and CTSS A-to-I RNA editing are induced under hypoxic and pro-inflammatory conditions in human endothelial cells.
Figure 5: Clinical implications of RNA-editing-controlled CTSS mRNA expression in patients with atherosclerotic vascular diseases.
Figure 6: ADAR1-induced CTSS Alu A-to-I RNA editing is associated with upregulated CTSS mRNA expression in human atherosclerotic plaques.

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Acknowledgements

This work was funded by the 'FFF–Innovation 2012' program of the J.W. Goethe University Frankfurt (K. Stellos), the August–Scheidel Stiftung (K. Stellos), the Excellence Cluster Cardio-Pulmonary System (ECCPS) (K. Stellos), the Else Kröner–Fresenius–Stiftung (K. Stellos), the LOEWE Center for Cell and Gene Therapy (State of Hessen) (K. Stellos), the German Center for Cardiovascular Research (DZHK) (K. Stellos) and the German Cardiac Society (K. Stellos). H.S. and S.D. are members of the cluster of excellence 'macromolecular complexes'. B.F., H.S. and S.D. are supported by DFG SFB902. The BiKE study (U.H.) was conducted with support from the Swedish Heart and Lung Foundation, the Swedish Research Council, Uppdrag Besegra Stroke, the Strategic Cardiovascular Programs of Karolinska Institutet and the Stockholm County Council, the Foundation for Strategic Research and the European Commission (CarTarDis, AtheroRemo, VIA and AtheroFlux projects). L.P.M. was supported by the Swedish Society for Medical Research (SSMF). The thoracic aortic aneurysm study (P.E.) was supported by the Swedish Research Council, the Swedish Heart–Lung Foundation and a donation by F. Lundberg. O.R. is supported by the LOEWE program 'Medical RNomics' (State of Hessen). The authors would like to thank I. Dikic (Goethe University Frankfurt) for providing us with the HeLa cells, A. Knau for expert technical support, G. Georgiopoulos for statistical consulting, R. Achangwa and M. Sachse for proofreading, M. Karakitsou for technical assistance in subclinical atherosclerosis assessment, and A. Mareti, C. Kritsioti and A. Kotsogianni for helping with the recruitment of patients of the PBMC cohort.

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Authors and Affiliations

  1. Institute of Cardiovascular Regeneration, Center of Molecular Medicine, Goethe University Frankfurt, Frankfurt, Germany

    Konstantinos Stellos, Aikaterini Gatsiou, David John, Federica Francesca Lunella, Nicolas Jaé, Carolin Amrhein, Reinier A Boon, Yosif Manavski, Shizuka Uchida, Jes-Niels Boeckel & Stefanie Dimmeler

  2. Department of Cardiology, Center of Internal Medicine, Goethe University Frankfurt, Frankfurt, Germany

    Konstantinos Stellos, Till Keller & Andreas M Zeiher

  3. German Center of Cardiovascular Research (Deutsches Zentrum für Herz-Kreislaufforschung; DZHK), Rhein–Main Partner Site,

    Konstantinos Stellos, Aikaterini Gatsiou, David John, Federica Francesca Lunella, Nicolas Jaé, Reinier A Boon, Yosif Manavski, Shizuka Uchida, Till Keller, Jes-Niels Boeckel, Andreas M Zeiher & Stefanie Dimmeler

  4. DZHK), Rhein–Main Partner Site, Frankfurt, Germany

    Konstantinos Stellos, Aikaterini Gatsiou, David John, Federica Francesca Lunella, Nicolas Jaé, Reinier A Boon, Yosif Manavski, Shizuka Uchida, Till Keller, Jes-Niels Boeckel, Andreas M Zeiher & Stefanie Dimmeler

  5. Department of Clinical Therapeutics, Alexandra Hospital, National and Kapodistrian University of Athens, Athens, Greece

    Kimon Stamatelopoulos

  6. Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden

    Ljubica Perisic Matic & Ulf Hedin

  7. Institute of Biochemistry, University of Giessen, Giessen, Germany

    Oliver Rossbach & Albrecht Bindereif

  8. Department of Vascular Surgery, 1st Propaedeutic Department of Surgery, Hippocratio General Hospital, National and Kapodistrian University of Athens, Athens, Greece

    Frangiska Sigala

  9. Institute for Organic Chemistry and Chemical Biology, Center for Biomolecular Magnetic Resonance, Goethe University Frankfurt, Frankfurt, Germany

    Boris Fürtig & Harald Schwalbe

  10. Laboratory of Functional Genomics and Systems Biology, Max Delbrück Center for Molecular Medicine Berlin–Buch, Berlin, Germany

    Xintian You & Wei Chen

  11. Department of Molecular Medicine and Surgery, Cardiothoracic Surgery Unit, Karolinska Institute, Stockholm, Sweden

    Anders Franco-Cereceda

  12. Department of Medicine, Cardiovascular Medicine Unit, Karolinska Institute, Stockholm, Sweden

    Lars Maegdefessel & Per Eriksson

  13. Department of Vascular and Endovascular Surgery, Technical University Munich, Munich, Germany

    Lars Maegdefessel

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Contributions

K. Stellos and S.D. designed and guided research; K. Stellos, A.G., L.P.M., F.F.L., C.A. and Y.M. performed research; K. Stellos, A.G., K. Stamatelopoulos, L.P.M., F.F.L., J.-N.B., P.E., U.H. and S.D. analyzed data; T.K. recruited the pilot PBMC cohort; K. Stamatelopoulos recruited the validation PBMC cohort and performed the assessment of subclinical atherosclerosis; F.S., L.P.M. and U.H. provided the control arteries and the carotid atherosclerotic plaque tissues; X.Y. and W.C. performed RNA-seq; D.J. and S.U. performed the bioinformatic analysis; N.J., D.J., O.R., W.C. and A.B. performed and analyzed the iCLIP experiments; A.F.-C. and P.E. provided the human aortic aneurysm tissues; A.G., K. Stamatelopoulos, L.P.M., R.A.B., L.M., B.F., H.S., P.E., U.H., A.M.Z. and S.D. gave conceptual advice; and K. Stellos drafted the paper with input from all authors.

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Correspondence to Konstantinos Stellos or Stefanie Dimmeler.

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Stellos, K., Gatsiou, A., Stamatelopoulos, K. et al. Adenosine-to-inosine RNA editing controls cathepsin S expression in atherosclerosis by enabling HuR-mediated post-transcriptional regulation. Nat Med 22, 1140–1150 (2016). https://doi.org/10.1038/nm.4172

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