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Published August 2020 | public
Journal Article

Ubiquitin-dependent proteasomal degradation of AMPK gamma subunit by Cereblon inhibits AMPK activity


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.

Additional Information

© 2020 Published by Elsevier B.V. Received 16 November 2019, Revised 12 April 2020, Accepted 19 April 2020, Available online 22 April 2020. We thank Dr. Jong Yeon Kwang (Korea Research Institute of Chemical Technology) for kindly providing us with the TD-165. This work was supported by grants for the Korea Healthcare Technology Research and Development Project (HI13C1412), Ministry of Health and Welfare, GIST Research Institute (GRI), funded by the GIST in 2019, and Cell Logistics Research Center, National Research Foundation of Korea (NRF-2019R1A2C2087565). CRediT authorship contribution statement: Seung-Joo Yang:Investigation, Validation, Formal analysis, Writing - original draft.Seung-Je Jeon:Investigation, Validation.Thang Van Nguyen:Investigation, Validation.Raymond J. Deshaies:Investigation, Writing - review & editing.Chul-Seung Park:Conceptualization, Writing - review & editing, Supervision.Kwang Min Lee:Conceptualization, Investigation, Validation, Writing - review & editing, Supervision. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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August 22, 2023
October 20, 2023