CUL5 (cullin 5) functions as a core component of cullin-RING E3 ubiquitin ligase complexes that regulate protein degradation through the ubiquitin-proteasome system. CUL5 forms multiprotein complexes with various substrate adaptors including ASB proteins, SOCS proteins, and ARIH2 to target specific proteins for ubiquitination and subsequent proteasomal degradation 123. The protein plays critical roles in diverse cellular processes including epigenetic regulation, where CUL5-ASB7 promotes SUV39H1 degradation to maintain H3K9me3 homeostasis 1, and metabolic regulation, where CUL5-ASB11 drives purinosome assembly through PAICS ubiquitination 2. CUL5 is particularly relevant in cancer biology and immunotherapy. In small-cell lung cancer, CUL5 deficiency stabilizes integrin β1, promoting metastasis through FAK/SRC signaling 3. Conversely, CUL5 knockout enhances CAR-T cell effector functions via JAK/STAT pathway modulation 4 and improves NK cell anti-tumor immunity through IL-15R stabilization 5. CUL5 also regulates tau proteostasis in neurons 6 and serves as a host antiviral factor by promoting degradation of SARS-CoV-2 ORF9b protein 7. These diverse functions highlight CUL5's importance in cellular homeostasis and its potential as a therapeutic target.