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Estrogen-related receptor [alpha](ERR[alpha]) is one of the first orphan nuclear receptors to be identified, yet its physiological functions are still unclear. We show here that ERR[alpha] is an effector of the transcriptional coactivator PGC-1[alpha][peroxisome proliferator-activated receptor [gamma] (PPAR[gamma]) coactivator 1[alpha]], and that it regulates the expression of genes involved in oxidative phosphorylation and mitochondrial biogenesis. Inhibition of ERR[alpha] compromises the ability of PGC-1[alpha] to induce the expression of genes encoding mitochondrial proteins and to increase mitochondrial DNA content. A constitutively active form of ERR[alpha] is sufficient to elicit both responses. ERR[alpha] binding sites are present in the transcriptional control regions of ERR[alpha]/PGC-1[alpha]-induced genes and contribute to the transcriptional response to PGC-1[alpha]. The ERR[alpha]-regulated genes described here have been reported to be expressed at reduced levels in humans that are insulin-resistant. Thus, changes in ERR[alpha] activity could be linked to pathological changes in metabolic disease, such as diabetes.

A report that the peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) coactivator activity is potentiated by arginine methylation by protein arginine methyltransferase 1 (PRMT1), another nuclear receptor coactivator is presented. PGC-1alpha, a tissue-specific and inducible transcriptional coactivator for several nuclear receptors, plays a key role in energy metabolsim.

To find novel components in the glucocorticoid signal transduction pathway, we performed a yeast genetic screen to identify ligand-effect modulators (LEMs), proteins that modulate the cellular response to hormone. We isolated several mutants that conferred increased glucocorticoid receptor (GR) activity in response to dexamethasone and analyzed two of them in detail. These studies identify two genes, LEM3 and LEM4, which correspond to YNL323w and ERG6, respectively. LEM3 is a putative transmembrane protein of unknown function, and ERG6 is a methyhransferase in the ergosterol biosynthetic pathway. Analysis of null mutants indicates that LEM3 and ERG6 act at different steps in the GR signal transduction pathway.