RER1 (retention in endoplasmic reticulum sorting receptor 1) is a Golgi-localized sorting receptor that mediates retrograde retrieval of endoplasmic reticulum (ER) membrane proteins from the early Golgi compartment 1. The protein contains four transmembrane domains with a W-topology and localizes to the Golgi apparatus and ER-Golgi interface 1. Mechanistically, RER1 functions as a quality control receptor that retains and retrieves select cargo proteins, including unassembled immunoreceptor complexes and disease-related proteins. It interacts with DAP12 before assembly with TREM2, preventing premature plasma membrane transport 2. RER1 also regulates ER retention of PMP22 mutants causing Charcot-Marie-Tooth disease, working synergistically with calnexin and ubiquitin ligases in ER-associated degradation 3. Beyond protein trafficking, RER1 plays broader cellular roles: it maintains γ-secretase complex surface expression critical for Notch signaling during neural stem cell development 4, and regulates lipid metabolism in myeloid cells, controlling lipid droplet accumulation and metabolic gene expression 5. RER1 deletion impairs phagocytic activity and TREM2-DAP12 immune receptor signaling 2. Clinically, RER1 dysregulation associates with cancer progression—elevated expression enhances pancreatic cancer carcinogenesis under hypoxia 6, and RER1 variants correlate with ERBB2-driven breast cancer susceptibility and chemotherapy response 7. RER1 also appears in colorectal cancer prognostic signatures predicting survival and immune microenvironment composition 8.