Cereblon: promise and challenges for combating human diseases

Area of Science:

• Biochemistry
• Molecular Biology
• Cell Biology

Background:

• Cereblon (CRBN) functions as a key substrate recognition protein within the E3-ligase ubiquitin complex.
• CRBN's target specificity varies across tissues and cells, enabling regulation of diverse biological functions.
• Recent identification of novel endogenous CRBN substrates has broadened understanding of its physiological and pathological roles.

Purpose of the Study:

• To review the ubiquitin-proteasome system's principles related to CRBN.
• To discuss CRBN's regulation of physiological and pathological functions via endogenous substrates.
• To explore CRBN-mediated neo-substrates induced by immunomodulatory imide drugs and CRBN-based proteolysis-targeting chimeras (PROTACs).

Main Methods:

• Literature review of the ubiquitin-proteasome system.
• Analysis of studies on CRBN's endogenous and neo-substrate interactions.
• Examination of research on CRBN-based PROTAC development and therapeutic strategies.

Main Results:

• CRBN's diverse tissue-specific targets underscore its broad biological regulatory capacity.
• Novel CRBN substrates illuminate its involvement in various disease pathways.
• Immunomodulatory imide drugs induce neo-substrates, expanding CRBN's functional repertoire.
• CRBN-based PROTACs represent a promising therapeutic modality.

Conclusions:

• Understanding CRBN's substrate interactions is crucial for elucidating its roles in health and disease.
• CRBN-based PROTACs offer innovative strategies for targeted protein degradation and therapeutic development.
• This review provides insights for advancing disease treatment and biomedical applications of CRBN.