The Ubiquitination-Dependent and -Independent Functions of Cereblon in Cancer and Neurological Diseases

Cereblon (CRBN) mediates the teratogenic effect of thalidomide in zebrafish, chickens, and humans. It additionally modulates the anti-myeloma effect of the immunomodulatory drugs (IMiDs) thalidomide, lenalidomide, and pomalidomide. IMiDs bind to CRBN and recruit neo-substrates for their ubiquitination and proteasome-mediated degradation, which significantly expands the application of proteolysis-targeting chimeras (PROTACs) for targeted drug discovery. However, the underlying molecular mechanisms by which CRBN mediates the teratogenicity and anti-myeloma effect of IMiDs have not been fully elucidated. Furthermore, the normal physiological functions of endogenous CRBN have not been extensively studied, which prevents the thorough assessment of side effects of the CRBN ligand-based PROTACs in the treatment of cancer and neurological diseases. To advance our understanding of the diverse functions of CRBN, in this review, we will survey the ubiquitination-dependent and -independent functions of CRBN, summarize recent advances in the discovery of constitutive substrates and neo-substrates of CRBN, and explore the molecular functions of CRBN in cancer treatment and in the development of neurological diseases. We will also discuss the potential future directions toward the identification of CRBN substrates/interacting proteins and CRBN ligand-based drug discovery in the treatment of cancer and neurological diseases.