The estrogen-related receptor alpha: the oldest, yet an energetic orphan with robust biological functions

Ranhotra, Harmit S.

doi:10.3109/10799893.2010.487493

Cited by 45 publications

(35 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Besides its impact on the synthesis of nucleic acids within HCMV-infected cells by supporting the accumulation of nucleoside and deoxynucleoside mono-, di-, and triphosphates, ERRα is generally required for cells and tissues with high energy demand (55), and it is likely to impact viral replication and spread through additional effects on metabolism. ERRα promotes a Warburg-like effect by inducing a metabolic shift from oxidative phosphorylation to glycolysis (27), and it has also been shown to maintain the TCA cycle by inducing anaplerotic replenishment of TCA cycle metabolites (27).…”

Section: Discussionmentioning

confidence: 99%

Estrogen-related receptor α is required for efficient human cytomegalovirus replication

Hwang¹,

Purdy

Wu³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

An shRNA-mediated screen of the 48 human nuclear receptor genes identified multiple candidates likely to influence the production of human cytomegalovirus in cultured human fibroblasts, including the estrogen-related receptor α (ERRα), an orphan nuclear receptor. The 50-kDa receptor and a 76-kDa variant were induced posttranscriptionally following infection. Genetic and pharmacological suppression of the receptor reduced viral RNA, protein, and DNA accumulation, as well as the yield of infectious progeny. In addition, RNAs encoding multiple metabolic enzymes, including enzymes sponsoring glycolysis (enolase 1, triosephosphate isomerase 1, and hexokinase 2), were reduced when the function of ERRα was inhibited in infected cells. Consistent with the effect on RNAs, a substantial number of metabolites, which are normally induced by infection, were either not increased or were increased to a reduced extent in the absence of normal ERRα activity. We conclude that ERRα is needed for the efficient production of cytomegalovirus progeny, and we propose that the nuclear receptor contributes importantly to the induction of a metabolic environment that supports optimal cytomegalovirus replication.herpesvirus | metabolism | nuclear receptor | mass spectrometry H uman cytomegalovirus (HCMV) belongs to the β-herpesvirus subfamily, and although most healthy individuals remain asymptomatic subsequent to infection, the pathogen is a major contributor to birth defects and to life-threatening disease in immunocompromised patients (1-3). As with all viruses, HCMV depends on the host cell to provide macromolecular building blocks for virion production, and throughout the course of its evolution, HCMV has adapted to manipulate numerous fundamental cellular processes, including RNA accumulation (4), translation (5), metabolism (6, 7), secretory pathways (8), and the cell cycle (9).The nuclear receptor gene family, of which there are 48 members in the human genome, encodes transcription factors (10). Some bind to specific hydrophobic ligands such as steroids, vitamin D, fatty acids, and lipids, providing a means to sense changes in the extracellular or intracellular environment; others are "orphans" with no known ligand, and are often constitutively active (11). As transcription factors that modulate broad gene regulatory networks, nuclear receptors control numerous physiological processes, including aspects of metabolism (cell autonomously and at the whole-organism level), development, and cellular differentiation, cancer, circadian rhythm, and immunity (11).The first indication that nuclear receptor signaling modulates HCMV replication surfaced after the identification of a retinoic acid response element within the major immediate-early promoter (MIEP) that caused a dose-dependent response to retinoic acid in reporter assays (12). Retinoic acid was further shown to enhance viral DNA replication and progeny production in human embryonal carcinoma cells and foreskin fibroblasts (13,14). The ligand also exacerbated symptoms of infection,...

show abstract

Section: Discussionmentioning

confidence: 99%

Estrogen-related receptor α is required for efficient human cytomegalovirus replication

Hwang¹,

Purdy

Wu³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…These orphan receptors have homology to estrogen receptors and are thought to have constitutive transcriptional activity that is regulated by cofactor interactions with transcription factors such as PGC1 α / β (peroxisome proliferator-activated receptor gamma coactivator 1) and deacetylation by Sirt1 (sirtuin 1) (41). Expression of ERR β is not well characterized in the immune system, but ERR α is ubiquitously expressed in lymphocytes and macrophages.…”

Section: Transcriptional Regulators Of Metabolismmentioning

confidence: 99%

Metabolic Regulation of T Lymphocytes

MacIver

Michalek²,

Rathmell

2013

Annu. Rev. Immunol.

1,082

1,157

View full text Add to dashboard Cite

T cell activation leads to dramatic shifts in cell metabolism to protect against pathogens and to orchestrate the action of other immune cells. Quiescent T cells require predominantly ATP-generating processes, whereas proliferating effector T cells require high metabolic flux through growth-promoting pathways. Further, functionally distinct T cell subsets require distinct energetic and biosynthetic pathways to support their specific functional needs. Pathways that control immune cell function and metabolism are intimately linked, and changes in cell metabolism at both the cell and system levels have been shown to enhance or suppress specific T cell functions. As a result of these findings, cell metabolism is now appreciated as a key regulator of T cell function specification and fate. This review discusses the role of cellular metabolism in T cell development, activation, differentiation, and function to highlight the clinical relevance and opportunities for therapeutic interventions that may be used to disrupt immune pathogenesis.

show abstract

“…Estrogen-related receptor α (ERRα) belongs to a nuclear receptor superfamily characterized by their high levels of sequence identity to estrogen receptors, and the primary role of ERRα is in energy metabolism (9). A study has demonstrated that activation of the peroxisome proliferator-activated receptor g coactivator 1-α (PGC-1α)/ERRα pathway increases VEGF expression and angiogenesis in endothelial cells, which suggests that ERRα may be involved in the pathogenesis of DR (10).…”

Section: Introductionmentioning

confidence: 99%

Kaempferol targets estrogen‑related receptor α and suppresses the angiogenesis of human retinal endothelial cells under high glucose conditions

Zhang

2017

Exp Ther Med

View full text Add to dashboard Cite

Abstract. Diabetic retinopathy (DR) is the most common complication of diabetes and a major cause of new-onset blindness in the developed world. The present study aimed to examine the effect of kaempferol on high glucose-induced human retinal endothelial cells (HRECs) in vitro. The expression levels of various mRNAs and proteins were measured by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting, respectively. The target of kaempferol was determined using a luciferase reporter assay. In addition, HREC proliferation, migration and cell sprouting were determined using Cell Counting kit-8, wound scratch and tube formation assays, respectively. RT-qPCR and western blotting results showed that treatment with 30 mM glucose for 12, 24 and 48 h increased the expression level of estrogen-related receptor α (ERRα) mRNA and protein.The luciferase reporter assay demonstrated that kaempferol inhibited ERRα activity in HRECs. Compared with 5 mM normal glucose treatment, high (30 mM) glucose significantly promoted the proliferation, migration and tube formation of HRECs, which was antagonized by 10 and 30 µM kaempferol in a dose-dependent manner. Treatment with 30 mM glucose also increased the expression of vascular endothelial growth factor (VEGF) mRNA and protein, and the expression levels of VEGF mRNA and protein were suppressed by kaempferol (10 and 30 µM). Kaempferol (30 µM) treatment also increased the expression levels of thrombospondin 1 (TSP-1) and a disintegrin and metalloproteinase with thrombospondin motifs 1 (ADAMTS-1) mRNA; however, TSP-1 and ADAMTS-1 levels did not differ between high glucose and normal (5 mM) glucose conditions. The results of this study suggest that kaempferol targets ERRα and suppresses the angiogenesis of HRECs under high glucose conditions. Kaempferol may be a potential drug for use in controlling the progression of DR; however, in vivo studies are required to evaluate its efficacy and safety.

show abstract

The estrogen-related receptor alpha: the oldest, yet an energetic orphan with robust biological functions

Cited by 45 publications

References 57 publications

Estrogen-related receptor α is required for efficient human cytomegalovirus replication

Estrogen-related receptor α is required for efficient human cytomegalovirus replication

Metabolic Regulation of T Lymphocytes

Kaempferol targets estrogen‑related receptor α and suppresses the angiogenesis of human retinal endothelial cells under high glucose conditions

Contact Info

Product

Resources

About