Molecular Mechanism of Cereblon‐dependent Down Regulation 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 still unclear. 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. We further found that AMPK g subunit was ubiqutinated by CRBN and ubiquitination persisted in the presence of IMiDs. These results strongly suggest that CRBN negatively regulates the AMPK activity by recruiting AMPK complex to CRL and degrading its g subunit.Support or Funding InformationThis work was supported by GIST Research Institute (GRI) grant funded by the GIST in 2019This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.