The homeobox protein Prox1 is a negative modulator of ERRα/PGC-1α bioenergetic functions

Estrogen-related receptor alpha (ERR alpha) and proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha) play central roles in the transcriptional control of energy homeostasis, but little is known about factors regulating their activity. Here we identified the homeobox protein prospero-related homeobox 1 (Prox1) as one such factor. Prox1 interacts with ERRa and PGC-1 alpha, occupies promoters of metabolic genes on a genome-wide scale, and inhibits the activity of the ERR alpha/PGC-1 alpha complex. DNA motif analysis suggests that Prox1 interacts with the genome through tethering to ERR alpha and other factors. Importantly, ablation of Prox1 and ERR alpha have opposite effects on the respiratory capacity of liver cells, revealing an unexpected role for Prox1 in the control of energy homeostasis.