Background:Mitochondrial proapoptotic proteins such as SMAC, HtrA2, and ARTS promote apoptosis by antagonizing the inhibitor of apoptosis proteins (IAPs). Results: A novel anti-apoptotic E3 ubiquitin ligase, AREL1 was cloned and identified to interact with and ubiquitinate the IAP antagonists. Conclusion: AREL1 inhibits apoptosis through ubiquitinating the cytosolic IAP antagonists. Significance: AREL1-mediated degradation of IAP antagonists represents a new anti-apoptotic signaling pathway.