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

Nat Commun. 2020 Feb 19;11(1):965. doi: 10.1038/s41467-019-14143-9.


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.

Publication types

  • Research Support, Non-U.S. Gov't

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


  • Membrane Proteins
  • REEP5 protein, human
  • Calcium