Molecular Mechanism for Cereblon‐dependent Inhibition of AMP‐activated Protein Kinase

Cereblon (CRBN), initially identified as a target protein of human mental retardation, is a substrate receptor of cullin‐ring E3 ubiquitin ligase (CRL) and a primary target of thalidomide‐induced teratogenicity. We previously reported that CRBN can negatively regulate the functional activity of AMP‐activated protein kinase (AMPK) by binding to the a subunit of the AMPK complex. We also noticed that the exogenous expression of CRBN reduced the content of g subunit in AMPK complex. However, the molecular mechanism for the CRBN‐dependent reduction of g subunit from AMPK complex was not clear. Thus, we investigated the molecular mechanism of CRBN‐dependent inhibition of AMPK. We noticed that the amount of g subunit in AMPK complex was increased in Crbn‐knockout (KO) MEFs and the g subunit was degraded more rapidly in wild‐type MEFs than in Crbn‐KO MEFs. After treating MG132, a proteasome inhibitor, the g subunit is accumulated more rapidly in wild‐type MEFs compared to Crbn‐KO MEFs. Moreover, ectopic expression of CRBN promoted the degradation of g subunit in Crbn‐knockout MEFs only in the presence of a subunit. These results strongly suggest that CRBN negatively regulates the AMPK activity by recruiting AMPK complex to CRL and degrading its g subunit.