ARIH2 (ariadne RBR E3 ubiquitin protein ligase 2) is a RING-between-RING (RBR) E3 ubiquitin ligase that catalyzes protein ubiquitination and degradation through proteasomal pathways 1. The protein functions primarily as a negative regulator in multiple cellular processes by targeting proteins for degradation. ARIH2 operates through cullin-5-RING E3 ligase complexes (CRL5), where neddylation of CUL5 exposes ARIH2 binding sites and relieves its autoinhibition, enabling substrate ubiquitination 2. In immune regulation, ARIH2 controls IL-15 receptor signaling by mediating IL-15RB degradation, limiting natural killer cell activation and anti-tumor immunity 3. The ligase also regulates NLRP3 inflammasome activity by targeting the nucleotide-binding domain, inhibiting inflammasome assembly 4. In metabolic processes, ARIH2 contributes to muscle differentiation regulation through the FoxP1-Arih2 axis and protects PPARγ from degradation in brown adipose tissue development 56. ARIH2 generally exhibits tumor suppressive functions across various cancers 1. A de novo mutation in ARIH2 has been associated with autism spectrum disorder and intellectual disability, suggesting roles in neurodevelopment 7. Knockout of ARIH2 enhances NK cell anti-tumor activity, making it a potential immunotherapy target 8.