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REEP5 depletion causes sarco-endoplasmic reticulum vacuolization and cardiac functional defects

Author

Listed:
  • Shin-Haw Lee

    (Translational Biology and Engineering Program, Ted Rogers Centre for Heart Research
    University of Toronto)

  • Sina Hadipour-Lakmehsari

    (Translational Biology and Engineering Program, Ted Rogers Centre for Heart Research
    University of Toronto)

  • Harsha R. Murthy

    (Program in Developmental and Stem Cell Biology, The Hospital for Sick Children
    University of Toronto)

  • Natalie Gibb

    (Program in Developmental and Stem Cell Biology, The Hospital for Sick Children
    University of Toronto)

  • Tetsuaki Miyake

    (University of Toronto
    York University)

  • Allen C. T. Teng

    (Translational Biology and Engineering Program, Ted Rogers Centre for Heart Research
    University of Toronto)

  • Jake Cosme

    (Translational Biology and Engineering Program, Ted Rogers Centre for Heart Research
    University of Toronto)

  • Jessica C. Yu

    (Translational Biology and Engineering Program, Ted Rogers Centre for Heart Research
    University of Toronto)

  • Mark Moon

    (University of Toronto
    Ottawa Heart Institute)

  • SangHyun Lim

    (Donnelly Centre, University of Toronto
    Faculty of Medicine, University of Toronto Canada)

  • Victoria Wong

    (Donnelly Centre, University of Toronto)

  • Peter Liu

    (Ottawa Heart Institute)

  • Filio Billia

    (Toronto General Research Institute, University Health Network)

  • Rodrigo Fernandez-Gonzalez

    (Translational Biology and Engineering Program, Ted Rogers Centre for Heart Research
    University of Toronto)

  • Igor Stagljar

    (Donnelly Centre, University of Toronto
    Faculty of Medicine, University of Toronto Canada
    Faculty of Medicine, University of Toronto
    Mediterranean Institute for Life Sciences)

  • Parveen Sharma

    (University of Toronto
    University of Liverpool)

  • Thomas Kislinger

    (University of Toronto
    Princess Margaret Cancer Centre)

  • Ian C. Scott

    (Program in Developmental and Stem Cell Biology, The Hospital for Sick Children
    University of Toronto)

  • Anthony O. Gramolini

    (Translational Biology and Engineering Program, Ted Rogers Centre for Heart Research
    University of Toronto)

Abstract

The sarco-endoplasmic reticulum (SR/ER) plays an important role in the development and progression of many heart diseases. However, many aspects of its structural organization remain largely unknown, particularly in cells with a highly differentiated SR/ER network. Here, we report a cardiac enriched, SR/ER membrane protein, REEP5 that is centrally involved in regulating SR/ER organization and cellular stress responses in cardiac myocytes. In vitro REEP5 depletion in mouse cardiac myocytes results in SR/ER membrane destabilization and luminal vacuolization along with decreased myocyte contractility and disrupted Ca2+ cycling. Further, in vivo CRISPR/Cas9-mediated REEP5 loss-of-function zebrafish mutants show sensitized cardiac dysfunction upon short-term verapamil treatment. Additionally, in vivo adeno-associated viral (AAV9)-induced REEP5 depletion in the mouse demonstrates cardiac dysfunction. These results demonstrate the critical role of REEP5 in SR/ER organization and function as well as normal heart function and development.

Suggested Citation

  • Shin-Haw Lee & Sina Hadipour-Lakmehsari & Harsha R. Murthy & Natalie Gibb & Tetsuaki Miyake & Allen C. T. Teng & Jake Cosme & Jessica C. Yu & Mark Moon & SangHyun Lim & Victoria Wong & Peter Liu & Fil, 2020. "REEP5 depletion causes sarco-endoplasmic reticulum vacuolization and cardiac functional defects," Nature Communications, Nature, vol. 11(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-019-14143-9
    DOI: 10.1038/s41467-019-14143-9
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