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Molecular Mechanism for Cereblon‐dependent Inhibition of AMP‐activated Protein Kinase
Author(s) -
Yang SeungJoo,
Lee Kwang Min,
Jeon Je Seung je,
Park ChulSeung
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.883.11
Subject(s) - cereblon , ampk , mg132 , chemistry , protein subunit , ubiquitin ligase , microbiology and biotechnology , protein kinase a , ubiquitin , gamma subunit , proteasome , kinase , biochemistry , biology , proteasome inhibitor , gene
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.