Cereblon (CRBN), a substrate receptor for Cullin-ring E3 ubiquitin ligase (CRL), is a major target protein of immunomodulatory drugs. An earlier study demonstrated that CRBN directly interacts with the catalytic α subunit of AMP-activated protein kinase (AMPK), a master regulator of energy homeostasis, down-regulating the enzymatic activity of AMPK. However, it is not clear how CRBN modulates AMPK activity. To investigate the mechanism of CRBN-dependent AMPK inhibition, we measured protein levels of each AMPK subunit in brains, livers, lungs, hearts, spleens, skeletal muscles, testes, kidneys, and embryonic fibroblasts from wild-type and Crbn^(−/−) mice. Protein levels and stability of the regulatory AMPKγ subunit were increased in Crbn^(−/−) mice. Increased stability of AMPKγ in Crbn^(−/−) MEFs was dramatically reduced by exogenous expression of Crbn. In wild-type MEFs, the proteasomal inhibitor MG132 blocked degradation of AMPKγ. We also found that CRL4^(CRBN) directly ubiquitinated AMPKγ. Taken together, these findings suggest that CRL4^(CRBN) regulates AMPK through ubiquitin-dependent proteasomal degradation of AMPKγ
