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

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 alpha subunit leads to CRL4(CRBN)-dependent degradation of the gamma 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 alpha subunit remains unclear. Here, we show that thalidomide does not affect AMPK activation or the binding affinity between CRBN and the AMPK alpha 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 alpha subunit. The present results suggest that CRL4(CRBN) negatively regulates AMPK through a pathway independent from the CRBN-IMiD binding region.