Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

Science 312 (5781): 1763-1766

Copyright © 2006 by the American Association for the Advancement of Science

TRB3 Links the E3 Ubiquitin Ligase COP1 to Lipid Metabolism

Ling Qi,1* Jose E. Heredia,1* Judith Y. Altarejos,1 Robert Screaton,1 Naomi Goebel,1 Sherry Niessen,2 Ian X. MacLeod,2 Chong Wee Liew,3 Rohit N. Kulkarni,3 James Bain,4 Christopher Newgard,4 Michael Nelson,1 Ronald M. Evans,1 John Yates,2 Marc Montminy1{dagger}

Abstract: 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.

1 Peptide Biology Laboratories and Gene Expression Laboratories, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
2 The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
3 Joslin Diabetes Center, One Joslin Place, Boston, MA 02215, USA.
4 Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, 4321 Medical Park Drive, Suite 200, Durham, NC 27704, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: montminy{at}

TRIB1 downregulates hepatic lipogenesis and glycogenesis via multiple molecular interactions.
Y. Ishizuka, K. Nakayama, A. Ogawa, S. Makishima, S. Boonvisut, A. Hirao, Y. Iwasaki, T. Yada, Y. Yanagisawa, H. Miyashita, et al. (2014)
J. Mol. Endocrinol. 52, 145-158
   Abstract »    Full Text »    PDF »
Insulin Receptor Signaling in Normal and Insulin-Resistant States.
J. Boucher, A. Kleinridders, and C. R. Kahn (2014)
Cold Spring Harb Perspect Biol 6, a009191
   Abstract »    Full Text »    PDF »
Impaired Phosphorylation and Ubiquitination by p70 S6 Kinase (p70S6K) and Smad Ubiquitination Regulatory Factor 1 (Smurf1) Promote Tribbles Homolog 2 (TRIB2) Stability and Carcinogenic Property in Liver Cancer.
J. Wang, Y. Zhang, W. Weng, Y. Qiao, L. Ma, W. Xiao, Y. Yu, Q. Pan, and F. Sun (2013)
J. Biol. Chem. 288, 33667-33681
   Abstract »    Full Text »    PDF »
COP1 targets C/EBP{alpha} for degradation and induces acute myeloid leukemia via Trib1.
A. Yoshida, J.-y. Kato, I. Nakamae, and N. Yoneda-Kato (2013)
Blood 122, 1750-1760
   Abstract »    Full Text »    PDF »
Increased expression of STK25 leads to impaired glucose utilization and insulin sensitivity in mice challenged with a high-fat diet.
E. Cansby, M. Amrutkar, L. Manneras Holm, A. Nerstedt, A. Reyahi, E. Stenfeldt, J. Boren, P. Carlsson, U. Smith, J. R. Zierath, et al. (2013)
FASEB J 27, 3660-3671
   Abstract »    Full Text »    PDF »
PRMT5 modulates the metabolic response to fasting signals.
W.-W. Tsai, S. Niessen, N. Goebel, J. R. Yates III, E. Guccione, and M. Montminy (2013)
PNAS 110, 8870-8875
   Abstract »    Full Text »    PDF »
Interaction of Constitutive Photomorphogenesis 1 Protein with Protein-Tyrosine Phosphatase 1B Suppresses Protein-Tyrosine Phosphatase 1B Activity and Enhances Insulin Signaling.
W. Ren, Y. Sun, S. Cheema, and K. Du (2013)
J. Biol. Chem. 288, 10902-10913
   Abstract »    Full Text »    PDF »
Photomorphogenesis, B-Box Transcription Factors, and the Legacy of Magnus Holm.
C. Bowler, J. Botto, and X.-W. Deng (2013)
PLANT CELL 25, 1192-1195
   Full Text »    PDF »
Modulation of Fatty Acid Synthase Degradation by Concerted Action of p38 MAP Kinase, E3 Ligase COP1, and SH2-Tyrosine Phosphatase Shp2.
J. Yu, R. Deng, H. H. Zhu, S. S. Zhang, C. Zhu, M. Montminy, R. Davis, and G.-S. Feng (2013)
J. Biol. Chem. 288, 3823-3830
   Abstract »    Full Text »    PDF »
Role of TRIB3 in regulation of insulin sensitivity and nutrient metabolism during short-term fasting and nutrient excess.
J. Liu, W. Zhang, G. C. Chuang, H. S. Hill, L. Tian, Y. Fu, D. R. Moellering, and W. T. Garvey (2012)
Am J Physiol Endocrinol Metab 303, E908-E916
   Abstract »    Full Text »    PDF »
Role of TRIB3 in Diabetic and Overnutrition-Induced Atherosclerosis.
J. R. Sowers (2012)
Diabetes 61, 265-266
   Full Text »    PDF »
Silence of TRIB3 Suppresses Atherosclerosis and Stabilizes Plaques in Diabetic ApoE-/-/LDL Receptor-/- Mice.
Z.-h. Wang, Y.-y. Shang, S. Zhang, M. Zhong, X.-p. Wang, J.-t. Deng, J. Pan, Y. Zhang, and W. Zhang (2012)
Diabetes 61, 463-473
   Abstract »    Full Text »    PDF »
TRB3 interacts with SMAD3 promoting tumor cell migration and invasion.
F. Hua, R. Mu, J. Liu, J. Xue, Z. Wang, H. Lin, H. Yang, X. Chen, and Z. Hu (2011)
J. Cell Sci. 124, 3235-3246
   Abstract »    Full Text »    PDF »
Adipose tissue transcriptome changes during obesity development in female dogs.
R. W. Grant, B. M. Vester Boler, T. K. Ridge, T. K. Graves, and K. S. Swanson (2011)
Physiol Genomics 43, 295-307
   Abstract »    Full Text »    PDF »
During EPO or anemia challenge, erythroid progenitor cells transit through a selectively expandable proerythroblast pool.
A. Dev, J. Fang, P. Sathyanarayana, A. Pradeep, C. Emerson, and D. M. Wojchowski (2010)
Blood 116, 5334-5346
   Abstract »    Full Text »    PDF »
Transformation by Tribbles homolog 2 (Trib2) requires both the Trib2 kinase domain and COP1 binding.
K. Keeshan, W. Bailis, P. H. Dedhia, M. E. Vega, O. Shestova, L. Xu, K. Toscano, S. N. Uljon, S. C. Blacklow, and W. S. Pear (2010)
Blood 116, 4948-4957
   Abstract »    Full Text »    PDF »
TRB3 is stimulated in diabetic kidneys, regulated by the ER stress marker CHOP, and is a suppressor of podocyte MCP-1.
E. Morse, J. Schroth, Y.-H. You, D. P. Pizzo, S. Okada, S. RamachandraRao, V. Vallon, K. Sharma, and R. Cunard (2010)
Am J Physiol Renal Physiol 299, F965-F972
   Abstract »    Full Text »    PDF »
TRB3: an oxidant stress-induced pseudokinase with a potential to negatively modulate MCP-1 cytokine in diabetic nephropathy.
Y. S. Kanwar (2010)
Am J Physiol Renal Physiol 299, F963-F964
   Full Text »    PDF »
Trib1 links the MEK1/ERK pathway in myeloid leukemogenesis.
T. Yokoyama, Y. Kanno, Y. Yamazaki, T. Takahara, S. Miyata, and T. Nakamura (2010)
Blood 116, 2768-2775
   Abstract »    Full Text »    PDF »
Differential ability of Tribbles family members to promote degradation of C/EBP{alpha} and induce acute myelogenous leukemia.
P. H. Dedhia, K. Keeshan, S. Uljon, L. Xu, M. E. Vega, O. Shestova, M. Zaks-Zilberman, C. Romany, S. C. Blacklow, and W. S. Pear (2010)
Blood 116, 1321-1328
   Abstract »    Full Text »    PDF »
Control of Adipose Tissue Inflammation Through TRB1.
A. Ostertag, A. Jones, A. J. Rose, M. Liebert, S. Kleinsorg, A. Reimann, A. Vegiopoulos, M. B. Diaz, D. Strzoda, M. Yamamoto, et al. (2010)
Diabetes 59, 1991-2000
   Abstract »    Full Text »    PDF »
Mammalian Tribbles homolog 3 impairs insulin action in skeletal muscle: role in glucose-induced insulin resistance.
J. Liu, X. Wu, J. L. Franklin, J. L. Messina, H. S. Hill, D. R. Moellering, R. G. Walton, M. Martin, and W. T. Garvey (2010)
Am J Physiol Endocrinol Metab 298, E565-E576
   Abstract »    Full Text »    PDF »
Molecular basis for antagonism between PDGF and the TGF{beta} family of signalling pathways by control of miR-24 expression.
M. C. Chan, A. C. Hilyard, C. Wu, B. N. Davis, N. S. Hill, A. Lal, J. Lieberman, G. Lagna, and A. Hata (2010)
EMBO J. 29, 559-573
   Abstract »    Full Text »    PDF »
Ubiquitin C-terminal hydrolase-L3-knockout mice are resistant to diet-induced obesity and show increased activation of AMP-activated protein kinase in skeletal muscle.
R. Setsuie, M. Suzuki, T. Kabuta, H. Fujita, S. Miura, N. Ichihara, D. Yamada, Y.-L. Wang, O. Ezaki, Y. Suzuki, et al. (2009)
FASEB J 23, 4148-4157
   Abstract »    Full Text »    PDF »
E3 ubiquitin ligase COP1 regulates the stability and functions of MTA1.
D.-Q. Li, K. Ohshiro, S. D. N. Reddy, S. B. Pakala, M.-H. Lee, Y. Zhang, S. K. Rayala, and R. Kumar (2009)
PNAS 106, 17493-17498
   Abstract »    Full Text »    PDF »
Aldo-keto Reductase Family 1 Member B10 Promotes Cell Survival by Regulating Lipid Synthesis and Eliminating Carbonyls.
C. Wang, R. Yan, D. Luo, K. Watabe, D.-F. Liao, and D. Cao (2009)
J. Biol. Chem. 284, 26742-26748
   Abstract »    Full Text »    PDF »
The Small Molecule Phenamil Induces Osteoblast Differentiation and Mineralization.
K. W. Park, H. Waki, W.-K. Kim, B. S. J. Davies, S. G. Young, F. Parhami, and P. Tontonoz (2009)
Mol. Cell. Biol. 29, 3905-3914
   Abstract »    Full Text »    PDF »
Skeletal Muscle-Specific Deletion of Lipoprotein Lipase Enhances Insulin Signaling in Skeletal Muscle but Causes Insulin Resistance in Liver and Other Tissues.
H. Wang, L. A. Knaub, D. R. Jensen, D. Young Jung, E.-G. Hong, H.-J. Ko, A. M. Coates, I. J. Goldberg, B. A. de la Houssaye, R. C. Janssen, et al. (2009)
Diabetes 58, 116-124
   Abstract »    Full Text »    PDF »
COP1 Functions as a FoxO1 Ubiquitin E3 Ligase to Regulate FoxO1-mediated Gene Expression.
S. Kato, J. Ding, E. Pisck, U. S. Jhala, and K. Du (2008)
J. Biol. Chem. 283, 35464-35473
   Abstract »    Full Text »    PDF »
EPO receptor circuits for primary erythroblast survival.
P. Sathyanarayana, A. Dev, J. Fang, E. Houde, O. Bogacheva, O. Bogachev, M. Menon, S. Browne, A. Pradeep, C. Emerson, et al. (2008)
Blood 111, 5390-5399
   Abstract »    Full Text »    PDF »
Opposite Regulation of CD36 Ubiquitination by Fatty Acids and Insulin: EFFECTS ON FATTY ACID UPTAKE.
J. Smith, X. Su, R. El-Maghrabi, P. D. Stahl, and N. A. Abumrad (2008)
J. Biol. Chem. 283, 13578-13585
   Abstract »    Full Text »    PDF »
TRB3 suppresses adipocyte differentiation by negatively regulating PPAR{gamma} transcriptional activity.
Y. Takahashi, N. Ohoka, H. Hayashi, and R. Sato (2008)
J. Lipid Res. 49, 880-892
   Abstract »    Full Text »    PDF »
Genetic Dissociation of Ethanol Sensitivity and Memory Formation in Drosophila melanogaster.
H. LaFerriere, D. J. Guarnieri, D. Sitaraman, S. Diegelmann, U. Heberlein, and T. Zars (2008)
Genetics 178, 1895-1902
   Abstract »    Full Text »    PDF »
Aldo-keto Reductase Family 1 B10 Affects Fatty Acid Synthesis by Regulating the Stability of Acetyl-CoA Carboxylase-{alpha} in Breast Cancer Cells.
J. Ma, R. Yan, X. Zu, J.-M. Cheng, K. Rao, D.-F. Liao, and D. Cao (2008)
J. Biol. Chem. 283, 3418-3423
   Abstract »    Full Text »    PDF »
Methionine restriction effects on 11 -HSD1 activity and lipogenic/lipolytic balance in F344 rat adipose tissue.
C. E. Perrone, D. A. L. Mattocks, G. Hristopoulos, J. D. Plummer, R. A. Krajcik, and N. Orentreich (2008)
J. Lipid Res. 49, 12-23
   Abstract »    Full Text »    PDF »
Trans-10, cis-12 conjugated linoleic acid activates the integrated stress response pathway in adipocytes.
P. C. LaRosa, J.-J. M. Riethoven, H. Chen, Y. Xia, Y. Zhou, M. Chen, J. Miner, and M. E. Fromm (2007)
Physiol Genomics 31, 544-553
   Abstract »    Full Text »    PDF »
TRB3 Blocks Adipocyte Differentiation through the Inhibition of C/EBP{beta} Transcriptional Activity.
O. Bezy, C. Vernochet, S. Gesta, S. R. Farmer, and C. R. Kahn (2007)
Mol. Cell. Biol. 27, 6818-6831
   Abstract »    Full Text »    PDF »
Enhanced TLR-mediated NF-IL6-dependent gene expression by Trib1 deficiency.
M. Yamamoto, S. Uematsu, T. Okamoto, Y. Matsuura, S. Sato, H. Kumar, T. Satoh, T. Saitoh, K. Takeda, K. J. Ishii, et al. (2007)
J. Exp. Med. 204, 2233-2239
   Abstract »    Full Text »    PDF »
TRB2, a Mouse Tribbles Ortholog, Suppresses Adipocyte Differentiation by Inhibiting AKT and C/EBPbeta.
T. Naiki, E. Saijou, Y. Miyaoka, K. Sekine, and A. Miyajima (2007)
J. Biol. Chem. 282, 24075-24082
   Abstract »    Full Text »    PDF »
A Novel Regulatory Mechanism of the Bone Morphogenetic Protein (BMP) Signaling Pathway Involving the Carboxyl-Terminal Tail Domain of BMP Type II Receptor.
M. C. Chan, P. H. Nguyen, B. N. Davis, N. Ohoka, H. Hayashi, K. Du, G. Lagna, and A. Hata (2007)
Mol. Cell. Biol. 27, 5776-5789
   Abstract »    Full Text »    PDF »
Cooperative interactions between CBP and TORC2 confer selectivity to CREB target gene expression.
K. Ravnskjaer, H. Kester, Y. Liu, X. Zhang, D. Lee, J. R. Yates III, and M. Montminy (2007)
EMBO J. 26, 2880-2889
   Abstract »    Full Text »    PDF »
TRB3 Inhibits the Transcriptional Activation of Stress-regulated Genes by a Negative Feedback on the ATF4 Pathway.
C. Jousse, C. Deval, A.-C. Maurin, L. Parry, Y. Cherasse, C. Chaveroux, R. Lefloch, P. Lenormand, A. Bruhat, and P. Fafournoux (2007)
J. Biol. Chem. 282, 15851-15861
   Abstract »    Full Text »    PDF »
Genetic Deletion of Trb3, the Mammalian Drosophila tribbles Homolog, Displays Normal Hepatic Insulin Signaling and Glucose Homeostasis.
H. Okamoto, E. Latres, R. Liu, K. Thabet, A. Murphy, D. Valenzeula, G. D. Yancopoulos, T. N. Stitt, D. J. Glass, and M. W. Sleeman (2007)
Diabetes 56, 1350-1356
   Abstract »    Full Text »    PDF »
Genetically Altered Expression of Spermidine/Spermine N1-Acetyltransferase Affects Fat Metabolism in Mice via Acetyl-CoA.
J. Jell, S. Merali, M. L. Hensen, R. Mazurchuk, J. A. Spernyak, P. Diegelman, N. D. Kisiel, C. Barrero, K. K. Deeb, L. Alhonen, et al. (2007)
J. Biol. Chem. 282, 8404-8413
   Abstract »    Full Text »    PDF »
Cell signaling. A new way to burn fat..
J. G. Neels and J. M. Olefsky (2006)
Science 312, 1756-1758
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882