Towards a unified molecular mechanism for ligand-dependent activation of NR4A-RXR heterodimers
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eLife Assessment
This important study investigated whether the nuclear receptor Nur77 is regulated by a non-canonical mechanism of ligand-induced disruption of its interaction with RXRg, similar to the family member Nurr1. The overall evidence is solid, but additional mechanisms that have not been fully explored in this study might contribute as well. This manuscript will be of interest to scientists focusing on mechanisms of transcriptional regulation.
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Abstract
Abstract
A subset of nuclear receptors (NRs) function as permissive heterodimers with retinoid X receptor (RXR), defined by transcriptional activation in response to binding RXR agonist ligands. Permissive NR-RXR activation operates via a classical pharmacological mechanism, where binding of an RXR agonist increases coactivator recruitment to the heterodimer. However, we previously demonstrated that transcriptional activation of permissive Nurr1-RXRα (NR4A2-NR2B1) heterodimers by an RXR ligand set, which included pharmacological RXR agonists and selective Nurr1-RXRα agonists that function as antagonists of RXRα homodimers, occurs via a non-classical mechanism: ligand-binding domain (LBD) heterodimer dissociation (Yu et al., 2023). Here, we extend mechanistic ligand profiling of the same RXR ligand set to Nur77-RXRγ (NR4A1-NR2B3), which is evolutionarily related to Nurr1-RXRα. Biochemical and NMR protein-protein interaction profiling along with cellular transcription studies indicate that the RXR ligand set, which lacks selective Nur77-RXRγ agonists, may influence Nur77-RXRγ transcriptional activation through both classical pharmacological activation and LBD heterodimer dissociation. However, upon reanalyzing our previously published data for Nurr1-RXRα, we found that the inclusion of selective Nurr1-RXRα agonists was essential for elucidating the LBD heterodimer dissociation mechanism. Our findings underscore the need for a more functionally diverse RXR ligand set to explore Nur77-RXRγ activation and unify LBD heterodimer dissociation as a potential targeting mechanism for NR4A-RXR heterodimers in neurodegenerative and inflammatory diseases.
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eLife Assessment
This important study investigated whether the nuclear receptor Nur77 is regulated by a non-canonical mechanism of ligand-induced disruption of its interaction with RXRg, similar to the family member Nurr1. The overall evidence is solid, but additional mechanisms that have not been fully explored in this study might contribute as well. This manuscript will be of interest to scientists focusing on mechanisms of transcriptional regulation.
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Reviewer #1 (Public review):
Summary:
This foundational study builds on prior work from this group to reveal the complexities underlying ligand-dependent RXRγ-Nur77 heterodimer formation, offering a compelling re-evaluation of their earlier conclusions. The authors examine how a library of RXR ligands influences the biophysical, structural, and functional properties of Nur77. They find that although the Nur77-RXRγ heterodimer shares notable functional similarities with the Nurr1-RXRα complex, it also exhibits unique features, notably, both dimer dissociation and classical agonist-driven activities. This work advances our understanding of the nuanced behaviors of nuclear receptor heterodimers, which have important implications for health and disease.
Strengths:
(1) Builds on previous work by providing a comprehensive analysis that …
Reviewer #1 (Public review):
Summary:
This foundational study builds on prior work from this group to reveal the complexities underlying ligand-dependent RXRγ-Nur77 heterodimer formation, offering a compelling re-evaluation of their earlier conclusions. The authors examine how a library of RXR ligands influences the biophysical, structural, and functional properties of Nur77. They find that although the Nur77-RXRγ heterodimer shares notable functional similarities with the Nurr1-RXRα complex, it also exhibits unique features, notably, both dimer dissociation and classical agonist-driven activities. This work advances our understanding of the nuanced behaviors of nuclear receptor heterodimers, which have important implications for health and disease.
Strengths:
(1) Builds on previous work by providing a comprehensive analysis that examines whether Nur77-RXRγ heterodimer formation parallels that of the Nurr1-RXRα complex.
(2) Systematic evaluation of a library of RXR ligands provides a broad survey of functional outputs.
(3) Careful reanalysis of previous work sheds new light on how NR4A heterodimers function.
Weaknesses:
(1) Some conclusions appear overstated or are not well substantiated by the work presented. It's unclear how the data support a non-classical mode of agonism, for example, based on the data shown.
(2) Some assays have relatively few replicates, with only two in some cases.
-
Reviewer #1 (Public review):
Summary:
This foundational study builds on prior work from this group to reveal the complexities underlying ligand-dependent RXRγ-Nur77 heterodimer formation, offering a compelling re-evaluation of their earlier conclusions. The authors examine how a library of RXR ligands influences the biophysical, structural, and functional properties of Nur77. They find that although the Nur77-RXRγ heterodimer shares notable functional similarities with the Nurr1-RXRα complex, it also exhibits unique features, notably, both dimer dissociation and classical agonist-driven activities. This work advances our understanding of the nuanced behaviors of nuclear receptor heterodimers, which have important implications for health and disease.
Strengths:
(1) Builds on previous work by providing a comprehensive analysis that …
Reviewer #1 (Public review):
Summary:
This foundational study builds on prior work from this group to reveal the complexities underlying ligand-dependent RXRγ-Nur77 heterodimer formation, offering a compelling re-evaluation of their earlier conclusions. The authors examine how a library of RXR ligands influences the biophysical, structural, and functional properties of Nur77. They find that although the Nur77-RXRγ heterodimer shares notable functional similarities with the Nurr1-RXRα complex, it also exhibits unique features, notably, both dimer dissociation and classical agonist-driven activities. This work advances our understanding of the nuanced behaviors of nuclear receptor heterodimers, which have important implications for health and disease.
Strengths:
(1) Builds on previous work by providing a comprehensive analysis that examines whether Nur77-RXRγ heterodimer formation parallels that of the Nurr1-RXRα complex.
(2) Systematic evaluation of a library of RXR ligands provides a broad survey of functional outputs.
(3) Careful reanalysis of previous work sheds new light on how NR4A heterodimers function.
Weaknesses:
(1) Some conclusions appear overstated or are not well substantiated by the work presented. It's unclear how the data support a non-classical mode of agonism, for example, based on the data shown.
(2) Some assays have relatively few replicates, with only two in some cases.
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