MIB2 is an E3 ubiquitin ligase that catalyzes nonproteolytic K63-linked ubiquitination of multiple substrates to regulate cellular signaling and trafficking. Its primary function involves mediating ubiquitination of Delta receptors to promote Notch signaling through receptor endocytosis, and ubiquitinating YAP/TAZ transcription factors in coordination with the FAT1 protocadherin to target them for proteasomal degradation 1. MIB2 also catalyzes K63-linked ubiquitination of PD-L1, facilitating its trafficking from the trans-Golgi network to the plasma membrane via RAB8-mediated exocytosis, enabling tumor immune evasion 2. In disease pathogenesis, MIB2 promotes non-small cell lung cancer progression by regulating cell cycle control through CDK2, CDK4, and cyclin B1 modulation 3. MIB2-mediated YAP/TAZ degradation acts as a tumor suppressor mechanism; loss of FAT1-MIB2 interaction increases YAP/TAZ protein levels and proliferation in head and neck squamous cell carcinoma 4. MIB2 also mediates ferroptosis in breast cancer by promoting GPX4 ubiquitination downstream of Nrf2 inhibition 5. Additionally, MIB2 regulates innate immunity by mediating RIG-I oligomerization and preventing its degradation during viral sensing 6, while Ebola virus VP35 exploits MIB2 interaction to suppress interferon responses 7. These diverse functions highlight MIB2's critical role in cancer progression, immune regulation, and viral pathogenesis.