Regulation of AMPK Activity by CRBN Is Independent of the Thalidomide-CRL4CRBN Protein Degradation Axis

Abstract

Cereblon (CRBN), a primary target of immune-modulatory imide drugs (IMiDs), functions as a substrate receptor in the CUL4-RBX1-DDB1-CRBN (known as CRL4CRBN) E3 ubiquitin ligase complex. Binding of IMiDs to CRBN redirects the CRL4CRBN E3 ubiquitin ligase to recruit or displace its substrates. Interaction between CRBN and the AMPK α subunit leads to CRL4CRBN-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 CRL4CRBN negatively regulates AMPK through a pathway independent from the CRBN-IMiD binding region.

Thalidomide interaction with inflammation in idiopathic pulmonary fibrosis

“…Cereblon is also involved in the pathogenesis of IPF (Kang et al 2021 ). Thalidomide and other IMiDs such as lenalidomide and pomalidomide inhibit the action of cereblon and allow the expression of AMPK (Yang et al 2021 ). Inhibition of AMPK is one of the mechanisms by which metformin inhibits proliferation and differentiation of human foetal lung fibroblast (Gu et al 2021 ; Chen et al 2022 ).…”