Regulation of AMPK Activity by CRBN Is Independent of the Thalidomide-CRL4^CRBN Protein Degradation Axis

• Main Authors: Seung-Joo Yang, Seungje Jeon, Jeong Won Baek, Kwang Min Lee, Chul-Seung Park
• Format: Article
• Language: English
• Published: MDPI AG 2021-05-01
• Series: Pharmaceuticals
• Subjects: thalidomide; AMP-activated protein kinase; cereblon
• Online Access: https://www.mdpi.com/1424-8247/14/6/512

Cereblon (CRBN), a primary target of immune-modulatory imide drugs (IMiDs), functions as a substrate receptor in the CUL4-RBX1-DDB1-CRBN (known as CRL4^CRBN) E3 ubiquitin ligase complex. Binding of IMiDs to CRBN redirects the CRL4^CRBN E3 ubiquitin ligase to recruit or displace its substrates. Interaction between CRBN and the AMPK α subunit leads to CRL4^CRBN-dependent degradation of the γ subunit and inhibits AMPK activity. However, the effect of thalidomide on the function of CRBN as a negative regulator of AMPK through interaction with the α subunit remains unclear. Here, we show that thalidomide does not affect AMPK activation or the binding affinity between CRBN and the AMPK α subunit. Thalidomide had no effect on AMPK activity independent of CRBN expression. The N-terminal region and C-terminal tail of CRBN, which is distinct from the IMiD binding site, were critical for interaction with the AMPK α subunit. The present results suggest that CRL4^CRBN negatively regulates AMPK through a pathway independent from the CRBN-IMiD binding region.