Cullin-4-RING E3 ubiquitin ligase complex containing cereblon (CRL4^CRBN^) (CRL4^CRBN^)

The Cullin-4-RING E3 ubiquitin ligase complex containing cereblon (CRL4^CRBN^) is a multi-subunit cellular machine that orchestrates ubiquitin-dependent degradation of specific proteins. Cereblon (CRBN), acting as the substrate receptor, determines which proteins are targeted for ubiquitination by interacting with the adaptor DDB1 and the scaffold protein Cullin-4. Drugs such as thalidomide and its analogs bind cereblon, reprogramming the complex’s substrate specificity to drive the selective degradation of key transcription factors (Ikaros and Aiolos), yielding anti-proliferative and immunomodulatory effects—particularly relevant in the treatment of multiple myeloma and other cancers. However, cereblon modulation can also disrupt embryonic development, leading to severe teratogenic effects. Cumulative evidence places this complex at the heart of multiple cellular processes, including cell signaling, protein turnover, development, and immunity.

Other names

Cereblon E3 ligase complexCRL4^CRBN^Cullin-4A/B-DDB1-Cereblon E3 complexCereblon E3 ubiquitin ligaseDDB1-CRBN complexCRBN-associated E3 ligase

Molecular glues (IMiDs): drugs bind to cereblon, alter substrate specificity, induce neo-substrate recruitment and degradation (e.g. Ikaros, Aiolos transcription factors); PROTACs: bifunctional molecules exploit cereblon’s substrate specificity for induced targeted protein degradation; Inhibition of immune cell function/proliferation by targeted proteasomal degradation of immune transcription factors.