Abstract
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.
Highlights
From the Laboratory of Molecular Biology, Cardiovascular Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892
This study demonstrated that this interaction required the leucine-rich motif of PGC-1␣ and the AF2 domain of ERR-␣
We have come to similar conclusions, and as noted in Fig. 1, in vivo, full-length ERR-␣ co-immunoprecipitated with PGC-1␣
Summary
Vol 277, No 52, Issue of December 27, pp. 50991–50995, 2002 Printed in U.S.A. Identification of a Specific Molecular Repressor of the Peroxisome Proliferator-activated Receptor ␥ Coactivator-1 ␣ (PGC-1␣)*. Specific molecular repressors of co-activators have not been described This postulated repressor appeared to bind to a potential leucine-rich motif contained within the inhibitory domain of PGC-1␣, which is distinct from the LXXLL motif that a variety of nuclear receptors interact with. The interaction of PGC-1␣ with this unidentified repressor has been postulated to be regulated in part by the p38/MAPK pathway [8, 21] Consistent with these studies, we report here the identification of a specific PGC-1␣ repressor and demonstrate that this molecule is the orphan nuclear receptor ERR-␣
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
