REEP5 depletion causes sarco-endoplasmic reticulum vacuolization and cardiac functional defects
Shin‐Haw Lee, Sina Hadipour‐Lakmehsari, Harsha Murthy, Natalie Gibb, Tetsuaki Miyake, Allen C. T. Teng, Jake Cosme, Jessica Yu, Mark Moon, Sang-Hyun Lim, Victoria Wong, Peter Liu, Filio Billia, Rodrigo Fernández‐González, Igor Štagljar, Parveen Sharma, Thomas Kislinger, Ian C. Scott, Anthony O. Gramolini
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 Ca 2+ 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.