USE1 (unconventional SNARE in the ER 1) is a bispecific E2 ubiquitin-conjugating enzyme that functions as the dedicated partner of the E1 enzyme UBA6 in intracellular protein modification pathways. Mechanistically, USE1 recognizes a polyalanine stretch within UBA6 and mediates the transfer of both ubiquitin and the ubiquitin-like modifier FAT10 to target proteins 1. This UBA6-USE1 axis plays critical roles in retrograde Golgi-to-ER transport and STING trafficking regulation, where USE1 loss enhances STING signaling by modulating intracellular transport dynamics 2. USE1 undergoes auto-FAT10ylation as a negative feedback mechanism to limit FAT10 conjugation through proteasomal degradation 3, though under inflammatory TNF conditions, FAT10 conjugation can proceed through alternative E2 enzymes independently of USE1 4. Clinically, USE1 is frequently overexpressed in lung cancer, where it promotes tumor progression 5. RNA interference-based targeting of USE1 effectively suppresses lung cancer cell proliferation, migration, and invasion through G1 cell cycle arrest and apoptosis induction 65. These findings establish USE1 as both a fundamental regulator of vesicular trafficking and ubiquitin-like modification, and as a promising therapeutic target for lung cancer treatment.