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

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, Filio Billia, Rodrigo Fernandez-Gonzalez, Igor Stagljar, Parveen Sharma, Thomas Kislinger, Ian C. Scott and Anthony O. Gramolini ()
Additional contact information
Shin-Haw Lee: Translational Biology and Engineering Program, Ted Rogers Centre for Heart Research
Sina Hadipour-Lakmehsari: Translational Biology and Engineering Program, Ted Rogers Centre for Heart Research
Harsha R. Murthy: Program in Developmental and Stem Cell Biology, The Hospital for Sick Children
Natalie Gibb: Program in Developmental and Stem Cell Biology, The Hospital for Sick Children
Tetsuaki Miyake: University of Toronto
Allen C. T. Teng: Translational Biology and Engineering Program, Ted Rogers Centre for Heart Research
Jake Cosme: Translational Biology and Engineering Program, Ted Rogers Centre for Heart Research
Jessica C. Yu: Translational Biology and Engineering Program, Ted Rogers Centre for Heart Research
Mark Moon: University of Toronto
SangHyun Lim: Donnelly Centre, University of Toronto
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
Igor Stagljar: Donnelly Centre, University of Toronto
Parveen Sharma: University of Toronto
Thomas Kislinger: University of Toronto
Ian C. Scott: Program in Developmental and Stem Cell Biology, The Hospital for Sick Children
Anthony O. Gramolini: Translational Biology and Engineering Program, Ted Rogers Centre for Heart Research

Nature Communications, 2020, vol. 11, issue 1, 1-20

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-019-14143-9

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