Downregulation of AMP-activated protein kinase by Cidea-mediated ubiquitination and degradation in brown adipose tissue.
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.
Qi
Jingzong
J
Protein Science Laboratory of Ministry of Education, Department of Biological Sciences and Biotechnology, Tsinghua University, Beijing, China.
Gong
Jingyi
J
Zhao
Tongjin
T
Zhao
Jie
J
Lam
Penny
P
Ye
Jing
J
Li
John Zhong
JZ
Wu
Jiawei
J
Zhou
Hai-Meng
HM
Li
Peng
P
D055372:AMP-Activated Protein Kinases; D017667:Adipocytes / Q000201:enzymology*; D002001:Adipose Tissue, Brown / Q000166:cytology / Q000201:enzymology*; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D004721:Endoplasmic Reticulum / Q000201:enzymology; D004789:Enzyme Activation; D004795:Enzyme Stability; D051379:Mice; D018345:Mice, Knockout; D009097:Multienzyme Complexes / Q000378:metabolism*; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D021122:Protein Subunits / Q000378:metabolism; D054875:Ubiquitination
D051017:Apoptosis Regulatory Proteins; C112510:Cidea protein, mouse; D009097:Multienzyme Complexes; D021122:Protein Subunits; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases