HEATR5B is a HEAT repeat-containing protein that functions as a component of clathrin-coated vesicles and the aftiphilin/p200/gamma-synergin complex, regulating AP1-mediated protein trafficking. It promotes motility of AP1-bound endosomal membranes by binding directly to the dynein tail and dynactin complex, thereby coordinating dynein-based transport to the Golgi apparatus 1. The protein also facilitates trafficking of transferrin, furin, and cathepsin D between the trans-Golgi network and endosomes. Beyond its canonical trafficking role, a HEATR5B-derived circular RNA encodes a novel protein variant (HEATR5B-881aa) that suppresses aerobic glycolysis in glioblastoma by phosphorylating JMJD5 and inhibiting PKM2 activity, suggesting potential therapeutic relevance in GBM 2. Clinically, biallelic hypomorphic mutations in HEATR5B cause pontocerebellar hypoplasia with neonatal seizures, severe intellectual disability, and motor delay, reflecting the protein's essential role in neural development 3. Additionally, truncating variants in HEATR5B show partial segregation with prostate cancer in familial BRCAX cases 4. HEATR5B function depends on fast-evolving cofactors that regulate both AP1 binding and intra-Golgi recycling 5.