AREL1 (apoptosis resistant E3 ubiquitin protein ligase 1) is a HECT family E3 ubiquitin ligase that functions as an anti-apoptotic regulator through multiple mechanisms 1. AREL1 catalyzes K11- and K33-linked polyubiquitin chains and specifically ubiquitinates pro-apoptotic proteins including SMAC, HtrA2, and ARTS in the cytosol, targeting them for proteasomal degradation 12. The protein contains an extended HECT domain with a unique loop structure and requires its N-terminal extended region for stability and catalytic activity 2. Beyond apoptosis regulation, AREL1 controls lysosomal positioning by establishing ER-lysosome membrane contacts through interaction with V-ATPase and catalyzing K33-linked ubiquitination of the V1B2 subunit, promoting perinuclear lysosomal clustering essential for proper lysosomal function 3. Disease relevance includes involvement in multiple system atrophy, where AREL1 expression is increased in patient brains associated with neuroinflammatory responses 4. AREL1 also protects vascular endothelial cells from TGF-β-induced apoptosis 5. Genome-wide association studies have identified AREL1 as a potential causal gene for major depressive disorder 67. AREL1 knockout mice exhibit age-dependent Purkinje cell loss and ataxic phenotypes, highlighting its importance in neuronal survival 3.