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

Authors: 
Lee S-H, Hadipour-Lakmehsari S, Murthy HR, Gibb N, Miyake T, Teng ACT, Cosme J, Yu JC, Moon M, Lim SH, Wong V, Liu P, Billia F, Fernandez-Gonzalez R, Stagljar I, Sharma P, Kislinger T, Scott IC, Gramolini AO
Citation: 
Nat Comm. 2020;11:965 doi:10.1038/s41467-019-14143-9
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.
Epub: 
Not Epub
Organism or Cell Type: 
zebrafish
Delivery Method: 
microinjection