REEP5 (receptor accessory protein 5) is an endoplasmic reticulum (ER) membrane-shaping protein that plays multifaceted roles in cellular homeostasis and disease pathophysiology. Structurally, REEP5 belongs to the REEP5-6 subfamily of membrane curvature-generating proteins 1 and functions as an ER tubule-shaping protein 2. Primary mechanistically, REEP5 regulates ER morphogenesis and organization in cardiomyocytes, where it is enriched 3. REEP5 depletion causes SR/ER membrane destabilization, luminal vacuolization, decreased myocyte contractility, and disrupted calcium cycling 3. Beyond ER organization, REEP5 mediates mitochondrial-ER membrane contact sites (MERCs) by dynamically interacting with Mitofusins 1/2, enabling mitochondrial "hitchhiking" on tubular ER and regulating mitochondrial reactive oxygen species production 2. REEP5 also functions as a GPCR accessory protein, enhancing CXCR1-mediated cellular responses and regulating receptor endocytosis 4. Clinically, REEP5 dysfunction associates with cardiac disease pathophysiology 1. REEP5 gene polymorphisms influence antidepressant treatment response in major depression disorder 5. Additionally, the REEP5/TRAM1 complex interacts with SARS-CoV-2 NSP3 and promotes viral replication 6, and REEP5 participates in ER-phagy pathways relevant to liver fibrosis 7.