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Role of CRBN in molecular and cellular mechanism of AMPK inhibition.

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