Downregulation of AMP-activated Protein Kinase by Cidea-mediated Ubiquitination and Degradation in Brown Adipose Tissue

EMBO J. 2008 Jun 4;27(11):1537-48. doi: 10.1038/emboj.2008.92. Epub 2008 May 15.

Abstract

We previously showed that Cidea(-/-) mice are resistant to diet-induced obesity through the upregulation of energy expenditure. The AMP-activated protein kinase (AMPK), consisting of catalytic alpha subunit and regulatory subunits beta and gamma, has a pivotal function in energy homoeostasis. We show here that AMPK protein levels and enzymatic activity were significantly increased in the brown adipose tissue of Cidea(-/-) mice. We also found that Cidea is colocalized with AMPK in the endoplasmic reticulum and forms a complex with AMPK in vivo through specific interaction with the beta subunit of AMPK, but not with the alpha or gamma subunit. When co-expressed with Cidea, the stability of AMPK-beta subunit was dramatically reduced due to increased ubiquitination-mediated degradation, which depends on a physical interaction between Cidea and AMPK. Furthermore, AMPK stability and enzymatic activity were increased in Cidea(-/-) adipocytes differentiated from mouse embryonic fibroblasts or preadipocytes. Our data strongly suggest that AMPK can be regulated by Cidea-mediated ubiquitin-dependent proteosome degradation, and provide a molecular explanation for the increased energy expenditure and lean phenotype in Cidea-null mice.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases
  • Adipocytes / enzymology*
  • Adipose Tissue, Brown / cytology
  • Adipose Tissue, Brown / enzymology*
  • Animals
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism*
  • Down-Regulation
  • Endoplasmic Reticulum / enzymology
  • Enzyme Activation
  • Enzyme Stability
  • Mice
  • Mice, Knockout
  • Multienzyme Complexes / metabolism*
  • Mutation
  • Protein Subunits / metabolism
  • Protein-Serine-Threonine Kinases / metabolism*
  • Ubiquitination*

Substances

  • Apoptosis Regulatory Proteins
  • Cidea protein, mouse
  • Multienzyme Complexes
  • Protein Subunits
  • Protein-Serine-Threonine Kinases
  • AMP-Activated Protein Kinases