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Transcriptional Regulation of ROS Homeostasis by the ERR Subfamily of Nuclear Receptors.

ABSTRACT: Reactive oxygen species (ROS) such as superoxide anion (O₂^•-) and hydrogen peroxide (H₂O₂) are generated endogenously by processes such as mitochondrial oxidative phosphorylation, or they may arise from exogenous sources like bacterial invasion. ROS can be beneficial (oxidative eustress) as signaling molecules but also harmful (oxidative distress) to cells when ROS levels become unregulated in response to physiological, pathological or pharmacological insults. Indeed, abnormal ROS levels have been shown to contribute to the etiology of a wide variety of diseases. Transcriptional control of metabolic genes is a crucial mechanism to coordinate ROS homeostasis. Therefore, a better understanding of how ROS metabolism is regulated by specific transcription factors can contribute to uncovering new therapeutic strategies. A large body of work has positioned the estrogen-related receptors (ERRs), transcription factors belonging to the nuclear receptor superfamily, as not only master regulators of cellular energy metabolism but, most recently, of ROS metabolism. Herein, we will review the role played by the ERRs as transcriptional regulators of ROS generation and antioxidant mechanisms and also as ROS sensors. We will assess how the control of ROS homeostasis by the ERRs can be linked to physiology and disease and the possible contribution of manipulating ERR activity in redox medicine.

SUBMITTER: Scholtes C

PROVIDER: S-EPMC7999130 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Two target gene activation pathways for orphan ERR nuclear receptors.

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The asymmetric binding of PGC-1? to the ERR? and ERR? nuclear receptor homodimers involves a similar recognition mechanism.

Project description:BackgroundPGC-1? is a crucial regulator of cellular metabolism and energy homeostasis that functionally acts together with the estrogen-related receptors (ERR? and ERR?) in the regulation of mitochondrial and metabolic gene networks. Dimerization of the ERRs is a pre-requisite for interactions with PGC-1? and other coactivators, eventually leading to transactivation. It was suggested recently (Devarakonda et al) that PGC-1? binds in a strikingly different manner to ERR? ligand-binding domains (LBDs) compared to its mode of binding to ERR? and other nuclear receptors (NRs), where it interacts directly with the two ERR? homodimer subunits.Methods/principal findingsHere, we show that PGC-1? receptor interacting domain (RID) binds in an almost identical manner to ERR? and ERR? homodimers. Microscale thermophoresis demonstrated that the interactions between PGC-1? RID and ERR LBDs involve a single receptor subunit through high-affinity, ERR-specific L3 and low-affinity L2 interactions. NMR studies further defined the limits of PGC-1? RID that interacts with ERRs. Consistent with these findings, the solution structures of PGC-1?/ERR? LBDs and PGC-1?/ERR? LBDs complexes share an identical architecture with an asymmetric binding of PGC-1? to homodimeric ERR.Conclusions/significanceThese studies provide the molecular determinants for the specificity of interactions between PGC-1? and the ERRs, whereby negative cooperativity prevails in the binding of the coactivators to these receptors. Our work indicates that allosteric regulation may be a general mechanism controlling the binding of the coactivators to homodimers.

| S-EPMC3706463 | biostudies-literature

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