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 ? 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 AMPK? subunit were increased in Crbn-/- mice. Increased stability of AMPK? in Crbn-/- MEFs was dramatically reduced by exogenous expression of Crbn. In wild-type MEFs, the proteasomal inhibitor MG132 blocked degradation of AMPK?. We also found that CRL4CRBN directly ubiquitinated AMPK?. Taken together, these findings suggest that CRL4CRBN regulates AMPK through ubiquitin-dependent proteasomal degradation of AMPK?.
Mesh Terms:
AMP-Activated Protein Kinases, Adaptor Proteins, Signal Transducing, Animals, Brain, Down-Regulation, Fibroblasts, HEK293 Cells, Heart, Homeostasis, Humans, Kidney, Liver, Lung, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Muscle, Skeletal, Spleen, Testis, Ubiquitin, Ubiquitin-Protein Ligase Complexes, Ubiquitin-Protein Ligases, Ubiquitination
Biochim Biophys Acta Mol Cell Res
Date: Dec. 01, 2019
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