The interacting domains in cereblon differentially modulate the immunomodulatory drug-mediated ubiquitination and degradation of its binding partners

Journal Article · Sat Dec 15 04:00:00 EST 2018 · Biochemical and Biophysical Research Communications

DOI:https://doi.org/10.1016/J.BBRC.2018.11.058· OSTI ID:23103648

Tao, Jing; Yang, Jing; Xu, Guoqiang ^[1]

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1. Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, 199 Ren'ai Road, Suzhou, Jiangsu, 215123 (China)

Highlights: • c-Jun, CLC-1, IKZF1, and MEIS2 interact with CRBN at different domains. • IMiDs differentially regulates the level of CRBN-interacting proteins. • IMiDs modulates the ubiquitination of CRBN-interacting proteins in three manners. • Interacting domains affect the IMiD-mediated regulation on CRBN-binding partners. Cereblon (CRBN), a substrate receptor of the cullin-4 RING E3 ligase (CRL4), has been utilized for the targeted protein degradation via small molecular weight CRBN modulators. However, it is unclear whether and how proteins that interact with CRBN at different domains are affected by these modulators. Here, we use CRBN and its four binding partners, c-Jun, chloride channel protein CLC-1, transcription factor IKZF1, and MEIS2, as model proteins to investigate the effect of immunomodulatory drugs (IMiDs) including thalidomide, lenalidomide, and pomalidomide, on their stability, ubiquitination, and interaction with CRBN. Together with previous discoveries, domain mapping experiment shows that these four proteins interact with CRBN at three distinct regions. Immunoblotting analyses reveal that the protein level of CRBN-binding partners could be enhanced, attenuated, or not affected by IMiDs. Interaction analyses and ubiquitination assay demonstrate that IMiDs modulate the interaction between CRBN and its binding partners in three distinct ways and thus differentially regulate their ubiquitination. This work suggests that the binding domain in CRBN is a critical factor which influences the regulation of IMiDs on the ubiquitination and stability of these CRBN-interacting partners.

• OSTI ID: 23103648
• Journal Information: Biochemical and Biophysical Research Communications, Journal Name: Biochemical and Biophysical Research Communications Journal Issue: 1-4 Vol. 507; ISSN 0006-291X; ISSN BBRCA9
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
CHLORIDES
DRUGS
LIGASES