Reep5, or Receptor expression-enhancing protein 5, is a member of the REEP family. It is an ER tubule-shaping protein that plays crucial roles in multiple biological processes. Reep5 is involved in maintaining the structure and function of the endoplasmic reticulum (ER) and is associated with pathways related to mitochondrial distribution, cardiac function, and viral replication [1,2,3]. Genetic models, such as gene knockout (KO) or conditional knockout (CKO) mouse models, are valuable for studying its functions.

In KO mouse models, Reep5 depletion leads to various functional defects. In cardiac myocytes, in vitro Reep5 depletion results in SR/ER membrane destabilization, luminal vacuolization, decreased myocyte contractility, and disrupted Ca2+ cycling. In vivo Nuclease technology-mediated Reep5 loss-of-function in zebrafish mutants shows sensitized cardiac dysfunction upon verapamil treatment, and AAV9-induced Reep5 depletion in mice also demonstrates cardiac dysfunction, highlighting its critical role in normal heart function and development [2]. In the context of mitochondrial regulation, Reep5 interacts with Mitofusins 1/2. Reep5 depletion reduces mitochondrial tethering and increases perinuclear localization, while increased expression facilitates mitochondrial distribution throughout the cytoplasm. Disrupting the MFN2-Reep5 interaction dynamics modulates mitochondrial reactive oxygen species (ROS) production [1]. Additionally, the Reep5/TRAM1 complex binds to SARS-CoV-2 NSP3 and promotes virus replication [3].

In conclusion, model-based research reveals that Reep5 is essential for maintaining ER and mitochondrial functions, as well as normal cardiac function. Reep5 KO/CKO mouse models have contributed to understanding its role in cardiac diseases and viral replication. These findings provide insights into potential therapeutic targets for heart-related disorders and antiviral strategies.