TRB3 links the E3 ubiquitin ligase COP1 to lipid metabolism.
During fasting, increased concentrations of circulating catecholamines promote the mobilization of lipid stores from adipose tissue in part by phosphorylating and inactivating acetyl-coenzyme A carboxylase (ACC), the rate-limiting enzyme in fatty acid synthesis. Here, we describe a parallel pathway, in which the pseudokinase Tribbles 3 (TRB3), whose abundance is increased during fasting, stimulates lipolysis by triggering the degradation of ACC in adipose tissue. TRB3 promoted ACC ubiquitination through an association with the E3 ubiquitin ligase constitutive photomorphogenic protein 1 (COP1). Indeed, adipocytes deficient in TRB3 accumulated larger amounts of ACC protein than did wild-type cells. Because transgenic mice expressing TRB3 in adipose tissue are protected from diet-induced obesity due to enhanced fatty acid oxidation, these results demonstrate how phosphorylation and ubiquitination pathways converge on a key regulator of lipid metabolism to maintain energy homeostasis.
Qi
Ling
L
Peptide Biology Laboratories and Gene Expression Laboratories, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
Heredia
Jose E
JE
Altarejos
Judith Y
JY
Screaton
Robert
R
Goebel
Naomi
N
Niessen
Sherry
S
Macleod
Ian X
IX
Liew
Chong Wee
CW
Kulkarni
Rohit N
RN
Bain
James
J
Newgard
Christopher
C
Nelson
Michael
M
Evans
Ronald M
RM
Yates
John
J
Montminy
Marc
M
D041721:3T3-L1 Cells; D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017667:Adipocytes / Q000378:metabolism; D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism*; D002001:Adipose Tissue, Brown / Q000166:cytology / Q000378:metabolism; D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002460:Cell Line; D004041:Dietary Fats / Q000008:administration & dosage; D004734:Energy Metabolism; D005215:Fasting; D005227:Fatty Acids / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D050356:Lipid Metabolism; D008066:Lipolysis; D051379:Mice; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000378:metabolism*; D009765:Obesity / Q000517:prevention & control; D010084:Oxidation-Reduction; D010766:Phosphorylation; D013851:Thinness; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D015430:Weight Gain
D018797:Cell Cycle Proteins; D004041:Dietary Fats; D005227:Fatty Acids; D009687:Nuclear Proteins; C474830:TRB3 protein, mouse; D025801:Ubiquitin; C471982:COP1 protein, mouse; D044767:Ubiquitin-Protein Ligases; D000103:Acetyl-CoA Carboxylase