ZFIN ID: ZDB-PUB-200222-3
REEP5 depletion causes sarco-endoplasmic reticulum vacuolization and cardiac functional defects
Lee, S.H., Hadipour-Lakmehsari, S., Murthy, H.R., Gibb, N., Miyake, T., Teng, A.C.T., Cosme, J., Yu, J.C., Moon, M., Lim, S., Wong, V., Liu, P., Billia, F., Fernandez-Gonzalez, R., Stagljar, I., Sharma, P., Kislinger, T., Scott, I.C., Gramolini, A.O.
Date: 2020
Source: Nature communications   11: 965 (Journal)
Registered Authors: Gibb, Natalie, Liu, Peter H., Scott, Ian
Keywords: none
MeSH Terms:
  • Animals
  • Calcium/metabolism
  • Cells, Cultured
  • Endoplasmic Reticulum Stress
  • Gene Knockout Techniques
  • Gene Silencing
  • Heart/growth & development
  • Heart/physiopathology*
  • Heart Diseases/metabolism
  • Heart Diseases/pathology
  • Heart Diseases/physiopathology
  • Humans
  • Intracellular Membranes/metabolism
  • Intracellular Membranes/pathology
  • Membrane Proteins/deficiency*
  • Membrane Proteins/genetics
  • Membrane Proteins/metabolism
  • Mice
  • Myocardial Contraction
  • Myocytes, Cardiac/metabolism
  • Myocytes, Cardiac/physiology
  • Sarcoplasmic Reticulum/genetics
  • Sarcoplasmic Reticulum/metabolism
  • Sarcoplasmic Reticulum/pathology*
  • Zebrafish
PubMed: 32075961 Full text @ Nat. Commun.
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.