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Originally published In Press as doi:10.1074/jbc.M210262200 on October 22, 2002

J. Biol. Chem., Vol. 277, Issue 52, 50991-50995, December 27, 2002
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Identification of a Specific Molecular Repressor of the Peroxisome Proliferator-activated Receptor gamma  Coactivator-1 alpha  (PGC-1alpha )*

Masaru IchidaDagger , Shino NemotoDagger , and Toren Finkel§

From the Laboratory of Molecular Biology, Cardiovascular Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892

The nuclear co-activator PGC-1alpha is a pivotal regulator of numerous pathways controlling both metabolism and overall energy homeostasis. Inappropriate increases in PGC-1alpha activity have been linked to a number of pathological conditions including heart failure and diabetes mellitus. Previous studies (Puigserver, P., Adelmant, G., Wu, Z., Fan, M., Xu, J., O'Malley, B., and Spiegelman, B. M. (1999) Science 286, 1368-1371) have demonstrated an inhibitory domain within PGC-1alpha that limits transcriptional activity. Using this inhibitory domain in a yeast two-hybrid screen, we demonstrate that PGC-1alpha directly associates with the orphan nuclear receptor estrogen-related receptor-alpha (ERR-alpha ). The binding of ERR-alpha to PGC-1alpha requires the C-terminal AF2 domain of ERR-alpha . PGC-1alpha and ERR-alpha have a similar pattern of expression in human tissues, with both being present predominantly in organs with high metabolic needs such as skeletal muscle and kidney. Similarly, we show that in mice physiological stimuli such as fasting coordinately induces PGC-1alpha and ERR-alpha transcription. We also demonstrate that under normal conditions PGC-1alpha is located within discrete nuclear speckles, whereas the expression of ERR-alpha results in PGC-1alpha redistributing uniformly throughout the nucleoplasm. Finally, we show that the expression of ERR-alpha can dramatically and specifically repress PGC-1alpha transcriptional activity. These results suggest a novel mechanism of transcriptional control wherein ERR-alpha can function as a specific molecular repressor of PGC-1alpha activity. In addition, our results suggest that other co-activators might also have specific repressors, thereby identifying another layer of combinatorial complexity in transcriptional regulation.

* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger These authors contributed equally to this work.

§ To whom correspondence should be addressed: National Institutes of Health, Bldg. 10/6N-240, 10 Center Dr., Bethesda, MD 20892-1622. Tel.: 301-402-4081; Fax: 301-402-9311; E-mail: finkelt@nih.gov.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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