RANBP2 (RAN binding protein 2), also known as Nup358, is the largest nucleoporin of the nuclear pore complex (NPC) and a multifunctional E3 SUMO-protein ligase 1. Primary functions include: (1) facilitating SUMO1 and SUMO2 conjugation to target proteins via UBE2I, including SUMOylation of PML at Lys-490 for proper assembly of PML nuclear bodies 1; (2) regulating nucleocytoplasmic transport through its F-G repeat domain that serves as a docking site for substrates and karyopherins 1; and (3) functioning as a specific docking site for exportin-1 in the nuclear export pathway 1. Beyond NPC localization, RANBP2 localizes to annulate lamellae, mitochondria-ER junctions, and kinetochores, contributing to cellular metabolism and mitotic progression 2. RANBP2 also regulates FOXO1 nuclear transport through temperature-sensitive mechanisms involving SUMO-modification of importin-7 and exportin-1 3. Dysregulation of RANBP2 is associated with serious pathologies. Mutations cause familial acute necrotizing encephalopathy (ANE), a severe neurological condition with high mortality 4. During influenza infection, 34% of pediatric ANE cases carried RANBP2 variants, contributing to disease susceptibility 5. RANBP2 is also implicated in cancer progression—it mediates bacterial pathogen-induced autophagy and HIF-1α activation in oral squamous cell carcinoma metastasis 6, and functions as a SUMO E3 ligase promoting STAT1 SUMOylation in melanoma immune evasion 7. Clinical significance extends to viral infections including COVID-19-associated ANE and potential roles in tissue preservation for transplantation.