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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}salk.edu

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