SPSB4 (splA/ryanodine receptor domain and SOCS box containing 4) functions as a substrate recognition component of SCF-like ECS E3 ubiquitin-protein ligase complexes that mediate ubiquitination and proteasomal degradation of target proteins 12. The protein contains a SPRY/B30.2 domain that recognizes specific peptide motifs, particularly D/E-I/L-N-N-N sequences, in target substrates 34. SPSB4 regulates multiple cellular processes through targeted protein degradation. It controls circadian rhythms by mediating ubiquitin-dependent degradation of the circadian repressor RevErbα/NR1D1, with SPSB1 and SPSB4 (but not SPSB2/SPSB3) regulating clock periodicity 5. SPSB4 also diminishes EphB2-mediated cell repulsive responses by promoting ubiquitination and degradation of the EphB2 cytoplasmic fragment, and its knockdown enhances these repulsive responses 6. Additionally, SPSB4 regulates adipocyte differentiation by targeting FOG-2 transcriptional cofactor for proteasomal degradation, recognizing a D-L-N-N-N sequence in FOG-2's N-terminal region 4. The protein acts as a bridge linking target substrates with ECS E3 ligase complex components ELOC and CUL5 2. SPSB4 expression has been implicated in gallbladder carcinogenesis associated with Salmonella infection 7.