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Aryl hydrocarbon receptor utilises cellular zinc signals to maintain the gut epithelial barrier
Dietary zinc and plant-derived aryl hydrocarbon receptor (AHR) agonists are involved in maintaining intestinal epithelium integrity. The authors show that combined supplementation with AHR ligands and zinc might be effective in preventing inflammatory gut disorders.
- Xiuchuan (Lucas) Hu
- , Wenfeng Xiao
- & Christer Hogstrand
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Article
| Open Access
Endothelial ERα promotes glucose tolerance by enhancing endothelial insulin transport to skeletal muscle
Estrogen has anti-diabetic effects via estrogen receptor alpha (ERα). Here, authors show that via coupled nuclear and non-nuclear actions, ERα in endothelial cells promotes insulin transport to skeletal muscle to foster normal glucose homeostasis.
- Anastasia Sacharidou
- , Ken Chambliss
- & Philip W. Shaul
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Article
| Open Access
Ligand dependent interaction between PC-TP and PPARδ mitigates diet-induced hepatic steatosis in male mice
Deletion of PC-TP has many beneficial effects, mostly ascribed to its role in regulating THEM2. Here, the authors show a novel interaction between PC-TP and PPARδ that explains aspects of the beneficial metabolic phenotype associated with PC-TP deletion.
- Samuel A. Druzak
- , Matteo Tardelli
- & Eric A. Ortlund
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Article
| Open Access
Structural basis of synthetic agonist activation of the nuclear receptor REV-ERB
The nuclear receptor REV-ERBα is a receptor for heme and plays a role in a range of physiological processes. Here, the authors provide the first structure of REV-ERB bound to a synthetic nonporphyrin ligand defining key mechanistic differences to how heme binds.
- Meghan H. Murray
- , Aurore Cecile Valfort
- & Thomas P. Burris
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Article
| Open Access
PPARγ lipodystrophy mutants reveal intermolecular interactions required for enhancer activation
Mutations in PPARγ lead to lipodystrophy, but the mechanisms by which the mutations affect the activity in chromatin is unknown. Here, Madsen, Broekema et al. showed that mutations affecting two intermolecular interactions compromise chromatin remodeling.
- Maria Stahl Madsen
- , Marjoleine F. Broekema
- & Eric Kalkhoven
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Article
| Open Access
Cryo-EM structure of the agonist-bound Hsp90-XAP2-AHR cytosolic complex
Aryl hydrocarbon receptor (AHR) is a sensor of the chemical environment including pollutants, diet components and metabolites. Here, authors determine the structure of the indirubin-bound AHR cytosolic complex providing mechanistic insights into ligand-binding promiscuity and selectivity.
- Jakub Gruszczyk
- , Loïc Grandvuillemin
- & William Bourguet
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Article
| Open Access
The nuclear receptor ERR cooperates with the cardiogenic factor GATA4 to orchestrate cardiomyocyte maturation
Mature cardiac muscle requires high mitochondrial ATP production and specialized contractile proteins. Here the authors demonstrate that cardiomyocyte-specific contractile maturation involves cooperation between the nuclear receptor ERRγ and cardiogenic transcription factor GATA4, but ERRγ controls metabolic genes independently.
- Tomoya Sakamoto
- , Kirill Batmanov
- & Daniel P. Kelly
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Article
| Open Access
Phase separation of Nur77 mediates celastrol-induced mitophagy by promoting the liquidity of p62/SQSTM1 condensates
How phase separation participates in mitophagy remains unclear. Here the authors show that Nur77 and p62/SQSTM1 through “head-to-head” and “tail-to-tail” interactions form membraneless condensates capable of sequestering dysfunctional mitochondria and tethering them to autolysosome for degradation.
- Shuang-zhou Peng
- , Xiao-hui Chen
- & Xiao-kun Zhang
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| Open Access
Nuclear transporter Importin-13 plays a key role in the oxidative stress transcriptional response
Importin superfamily member IPO13 mediates nuclear transport bidirectionally. Here the authors delineate the transcriptome of wild-type and IPO13-knockout mouse embryonic stem cells, revealing IPO13’s key role in the oxidative stress response through targeted transport of specific transcription factors.
- K. A. Gajewska
- , H. Lescesen
- & D. A. Jans
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| Open Access
Subtype-specific collaborative transcription factor networks are promoted by OCT4 in the progression of prostate cancer
Transcription factors (TFs) often form distinct networks to regulate transcriptional program during cancer progression. Here the authors show that OCT4 is a common transcriptional factor in two types of advanced PC and as such, OCT4 accelerates a TF complex formation with the FOXA1/AR in castration-resistant PC and NRF1 in neuroendocrine PC.
- Ken-ichi Takayama
- , Takeo Kosaka
- & Satoshi Inoue
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Article
| Open Access
NBR1 is a critical step in the repression of thermogenesis of p62-deficient adipocytes through PPARγ
p62 is a signaling hub protein that contributes to the control of energy expenditure. Here the authors investigate the relative roles of p62 and a similar protein, NBR1, and show that NBR1 is required for the repression of thermogenesis in adipocytes occurring in the absence of p62.
- Jianfeng Huang
- , Juan F. Linares
- & Jorge Moscat
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Article
| Open Access
Androgen signaling uses a writer and a reader of ADP-ribosylation to regulate protein complex assembly
Androgen receptor (AR) signaling is regulated by multiple post-translational modifications. Here, the authors identify the writer and reader enzymes for AR ADP-ribosylation and show how they modulate AR signaling output in prostate cancer cells.
- Chun-Song Yang
- , Kasey Jividen
- & Bryce M. Paschal
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Flexibility of intrinsically disordered degrons in AUX/IAA proteins reinforces auxin co-receptor assemblies
Auxin-mediated recruitment of AUX/IAAs by the F-box protein TIR1 prompts rapid AUX/IAA ubiquitylation and degradation. By resolving auxin receptor topology, the authors show that intrinsically disordered regions near the degrons of two Aux/IAA proteins reinforce complex assembly and position Aux/IAAs for ubiquitylation.
- Michael Niemeyer
- , Elena Moreno Castillo
- & Luz Irina A. Calderón Villalobos
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| Open Access
A molecular switch regulating transcriptional repression and activation of PPARγ
Structural studies of nuclear receptor transcription factors revealed that nearly all nuclear receptors share a conserved helix 12 dependent transcriptional activation mechanism. Here the authors present two crystal structures of peroxisome proliferator-activated receptor gamma (PPARγ) in an inverse agonist/corepressor-bound transcriptionally repressive conformation, where helix 12 is located within the orthosteric ligand-binding pocket instead, and discuss mechanistic implications.
- Jinsai Shang
- , Sarah A. Mosure
- & Douglas J. Kojetin
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Article
| Open Access
Definition of functionally and structurally distinct repressive states in the nuclear receptor PPARγ
The repressive states of peroxisome proliferator-activated receptor γ (PPARγ) are ill-defined, despite nuclear receptors being a major drug target. Here authors demonstrate multiple structurally distinct repressive states, providing a structural rationale for ligand bias in a nuclear receptor.
- Zahra Heidari
- , Ian M. Chrisman
- & Travis S. Hughes
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Article
| Open Access
Hsp70 and Hsp40 inhibit an inter-domain interaction necessary for transcriptional activity in the androgen receptor
Hsp chaperones stabilize the inactive conformation of androgen receptor (AR) and are released upon hormone-induced AR activation. Here, the authors locate the Hsp binding region on AR, and show that Hsp70 reduces AR aggregation and promotes AR degradation in cellular and mouse models of a neuromuscular disorder.
- Bahareh Eftekharzadeh
- , Varuna C. Banduseela
- & Xavier Salvatella
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Article
| Open Access
Molecular tuning of farnesoid X receptor partial agonism
The ligand-activated transcription factor farnesoid X receptor (FXR) acts as a cellular sensor for bile acids and is of interest as a drug target. Here the authors employ X-ray crystallography and NMR to characterize the molecular determinants of FXR agonists, antagonists and a partial agonist that drive FXR activation and antagonism.
- Daniel Merk
- , Sridhar Sreeramulu
- & Harald Schwalbe
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| Open Access
NLRC5 inhibits neointima formation following vascular injury and directly interacts with PPARγ
NLRC5 is known for its role in inflammation and antigen presentation. Here Luan et al. find that NLRC5 protects mice from intimal hyperplasia following vascular injury, and regulates the response of vascular smooth muscle cells to injury through direct interaction with PPARγ.
- Peipei Luan
- , Weixia Jian
- & Wenhui Peng
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| Open Access
Vps11 and Vps18 of Vps-C membrane traffic complexes are E3 ubiquitin ligases and fine-tune signalling
Endosomal fusion depends on the HOPS and CORVET complexes but whether and how their subunits modulate signal transduction is not fully understood. Here, the authors show that the HOPS/CORVET subunits Vps11 and Vps18 are E3 ubiquitin ligases that are involved in the regulation of ERα signalling.
- Gregory Segala
- , Marcela A. Bennesch
- & Didier Picard
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| Open Access
Hepatocyte-specific loss of GPS2 in mice reduces non-alcoholic steatohepatitis via activation of PPARα
Dysregulation of PPARα dependent fatty acid oxidation promotes hepatic steatosis. Here the authors show that GPS2 inhibits PPARα activity and that ablation of GPS2 ameliorates hepatic steatosis in mice.
- Ning Liang
- , Anastasius Damdimopoulos
- & Rongrong Fan
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| Open Access
The class 3 PI3K coordinates autophagy and mitochondrial lipid catabolism by controlling nuclear receptor PPARα
Peroxisome Proliferator Activated Receptor alpha (PPARα) drives fatty acid catabolism. Here, the authors show that in liver of autophagy deficient class 3 phosphoinositide 3-kinase mutant mice PPARα transcriptional repressors fail to degrade in lysosomes and accumulate leading to PPARα inhibition and blunted transcriptional responses during fasting.
- Anton Iershov
- , Ivan Nemazanyy
- & Ganna Panasyuk
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| Open Access
Recurrent activating mutations of PPARγ associated with luminal bladder tumors
Activation of the PPARγ/RXRα pathway in luminal bladder cancers has mainly been linked to PPARG gene amplifications and activating point mutations in RXRα. Here, the authors identify recurrent PPARγ mutations with similar effects and elucidate the structural basis for this mutational PPARγ activation.
- Natacha Rochel
- , Clémentine Krucker
- & Isabelle Bernard-Pierrot
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Article
| Open Access
Neurohormonal signaling via a sulfotransferase antagonizes insulin-like signaling to regulate a Caenorhabditis elegans stress response
Reduced insulin-like signaling is required for C. elegans response to many environmental stressors, but how distinct outcomes are achieved is unknown. The authors show that the cytosolic sulfotransferase SSU-1 controls neurohormonal signaling via NHR-1 to specify the animals’ osmotic stress response.
- Nicholas O. Burton
- , Vivek K. Dwivedi
- & H. Robert Horvitz
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| Open Access
A structural mechanism for directing corepressor-selective inverse agonism of PPARγ
Peroxisome proliferator-activated receptor gamma (PPARγ) is a target for insulin sensitizing drugs. Here the authors combine NMR, X-ray crystallography and MD simulations and report a structural mechanism for eliciting PPARγ inverse agonism, where coactivator binding is inhibited and corepressor binding promoted, which causes PPARγ repression.
- Richard Brust
- , Jinsai Shang
- & Douglas J. Kojetin
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Article
| Open Access
Multidomain architecture of estrogen receptor reveals interfacial cross-talk between its DNA-binding and ligand-binding domains
The human estrogen receptor alpha (hERα) is a hormone-responsive transcription factor. Here the authors combine small-angle X-ray scattering, hydroxyl radical protein footprinting and computational modeling and show that multidomain hERα adopts an L-shaped boot-like architecture revealing a cross-talk between its DNA-binding domain and Ligand-binding domain.
- Wei Huang
- , Yi Peng
- & Sichun Yang
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| Open Access
Defining a conformational ensemble that directs activation of PPARγ
Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor. Here the authors provide insights into PPARγ activation by combining fluorine (19F) NMR and molecular dynamics simulations to characterize the nuclear receptor conformational ensemble in solution and the response of this ensemble to ligand and coregulatory peptide binding.
- Ian M. Chrisman
- , Michelle D. Nemetchek
- & Travis S. Hughes
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Article
| Open Access
Caspase-1 cleaves PPARγ for potentiating the pro-tumor action of TAMs
Tumor associated macrophages (TAMs) promote cancer progression. Here, the author show that caspase-1 promotes TAMs differentiation by attenuating medium-chain acyl-CoA dehydrogenase activity and that inhibition of this axis results in suppression of tumour growth in a transgenic mouse model of breast cancer.
- Zhiyuan Niu
- , Qian Shi
- & Pingping Shen
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Article
| Open Access
RORα controls hepatic lipid homeostasis via negative regulation of PPARγ transcriptional network
Hepatic steatosis development may result from dysregulation of lipid metabolism, which is finely tuned by several transcription factors including the PPAR family. Here Kim et al. show that the nuclear receptor RORα inhibits PPARγ-mediated transcriptional activity by interacting with HDAC3 and competing for the promoters of lipogenic genes.
- Kyeongkyu Kim
- , Kyungjin Boo
- & Sung Hee Baek
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Modulation of nongenomic activation of PI3K signalling by tetramerization of N-terminally-cleaved RXRα
The transcription factor retinoid X receptor-alpha (RXRα) can also form homotetramers. Here the authors show that the anti-cancer agent K-80003 selectively inhibits the nongenomic action of N-terminally-cleaved RXRα in tumour cells by stabilizing its tetramerization but not that of full-length RXRα.
- Liqun Chen
- , Alexander E. Aleshin
- & Xiao-kun Zhang
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Article
| Open Access
Endothelial LRP1 regulates metabolic responses by acting as a co-activator of PPARγ
LDL receptor-related protein 1 (LRP1) is an endocytic receptor involved in cell signalling and energy homeostasis. Here Maoet al. demonstrate that endothelial Lrp1 modulates lipid and glucose metabolism by binding the nuclear receptor Pparγ and promoting its transcriptional activity.
- Hua Mao
- , Pamela Lockyer
- & Xinchun Pi
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Article
| Open Access
Nur77 suppresses hepatocellular carcinoma via switching glucose metabolism toward gluconeogenesis through attenuating phosphoenolpyruvate carboxykinase sumoylation
Gluconeogenesis is downregulated in hepatocellular carcinoma. Here, the authors show that nuclear receptor Nur77 acts as a tumour suppressor sustaining gluconeogenesis by enhancing phosphoenolpyruvate carboxykinase (PEPCK1) stability via regulating its interaction with the SUMO-conjugating enzyme Ubc9.
- Xue-li Bian
- , Hang-zi Chen
- & Qiao Wu
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Article
| Open Access
Tiam1/Rac1 complex controls Il17a transcription and autoimmunity
Tiam1 is a guanine nucleotide exchange factor for the Rho-family GTPase Rac1. Here, the authors show that nuclear Tiam1 and Rac1 bind to RORγt on the IL-17 promoter, activating its transcription, and that inhibiting Tiam1/Rac1 is beneficial in a mouse model of autoimmunity.
- Ahmed T. Kurdi
- , Ribal Bassil
- & Wassim Elyaman
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Article
| Open Access
Nuclear receptor NR5A2 controls neural stem cell fate decisions during development
The molecular signals regulating the decision of neural stem cells (NSC) to proliferate versus differentiate are unclear. Here, the authors identify the nuclear receptor NR5A2 as coordinating cell-cycle exit with differentiation of NSCs via direct actions on Ink4, Prox1, Notch1 and JAK/STAT.
- Athanasios Stergiopoulos
- & Panagiotis K. Politis
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Article
| Open Access
Ligand-binding domains of nuclear receptors facilitate tight control of split CRISPR activity
CRISPR-Cas9 has been widely used to manipulate genomes, however control over activity is necessary to explore transcriptional or epigenetic regulation. Here the authors use a split Cas9 fused to nuclear receptor ligand-binding domains to achieve tuneable Cas9 activity.
- Duy P. Nguyen
- , Yuichiro Miyaoka
- & James A. Wells
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Article
| Open Access
The TLX-miR-219 cascade regulates neural stem cell proliferation in neurodevelopment and schizophrenia iPSC model
Dysregulation of microRNAs has been implicated in neurodevelopmental disorders, including schizophrenia. Here the authors show that the TLX-miR-219 cascade regulates the proliferation of neural stem cells during normal development, and this pathway is dysregulated in a schizophrenia iPSC model.
- Kiyohito Murai
- , Guoqiang Sun
- & Yanhong Shi
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Article
| Open Access
Identification of an allosteric binding site for RORγt inhibition
Upon the binding of small ligands, nuclear receptors regulate the transcription of genes that are associated with a number of disease mechanisms. Here, the authors report on a novel allosteric ligand binding site on the nuclear receptor RORγt.
- Marcel Scheepstra
- , Seppe Leysen
- & Luc Brunsveld
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Article
| Open Access
Structural mechanism for signal transduction in RXR nuclear receptor heterodimers
Some nuclear receptors dimerize with retinoid X receptor to allow ligand-dependent signalling. Here, Kojetin et al.use structural and biophysical techniques to identify structural changes that guide these complex signalling networks.
- Douglas J. Kojetin
- , Edna Matta-Camacho
- & Kendall W. Nettles
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Transcriptional activation by the thyroid hormone receptor through ligand-dependent receptor recruitment and chromatin remodelling
The bimodal switch model posits that the unliganded thyroid hormone receptor (TR) binds chromatin stably. Here, the authors demonstrate ligand dependent recruitment of TR to chromatin, and further show that both unliganded and ligand-bound TR engages with chromatin in a highly dynamic manner.
- Lars Grøntved
- , Joshua J. Waterfall
- & Sheue-yann Cheng
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Article
| Open Access
LRH-1 mediates anti-inflammatory and antifungal phenotype of IL-13-activated macrophages through the PPARγ ligand synthesis
Macrophages activate gene expression of alternative activation program in response to IL-13. Here the authors show that Liver Receptor Homologue-1 regulates synthesis of lipid metabolites stimulating antifungal and repressing proinflammatory genes in macrophages exposed to IL-13 through PPAR activation.
- Lise Lefèvre
- , Hélène Authier
- & Agnès Coste
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An ecdysone-responsive nuclear receptor regulates circadian rhythms in Drosophila
The mammalian circadian clock is influenced by nuclear receptors such as Rev-Erb. Here Kumar et al. show that ecdysone-induced protein 75 (E75), a fly homologue of Rev-Erb, regulates circadian rhythms in Drosophila, and demonstrate that E75 protects the clock against environmental stressors.
- Shailesh Kumar
- , Dechun Chen
- & Amita Sehgal
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The palindromic DNA-bound USP/EcR nuclear receptor adopts an asymmetric organization with allosteric domain positioning
Nuclear receptors use DNA- and ligand-binding to regulate gene expression. Here, Maletta et al. report the first structural description of a full inverted repeat-bound nuclear receptor complex, which shows that the protein structure is asymmetric, despite the symmetry of the bound DNA.
- Massimiliano Maletta
- , Igor Orlov
- & Bruno P. Klaholz
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Cooperativity and equilibrium with FOXA1 define the androgen receptor transcriptional program
The pioneer factor FOXA1 contributes to androgen receptor (AR)-dependent gene expression by opening chromatin to facilitate AR binding. Here, Jin et al.show that because FOXA1 promotes AR association to many low-affinity sites, excessive FOXA1 can lead to reduced AR availability for specific sites.
- Hong-Jian Jin
- , Jonathan C. Zhao
- & Jindan Yu
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PPARγ-induced PARylation promotes local DNA demethylation by production of 5-hydroxymethylcytosine
Tet proteins control DNA demethylation, but how the DNA target regions are determined is unclear. Here the authors report that during adipocyte differentiation, PPARγ binds to the PPAR-response element and recruits Tet proteins, thereby inducing local DNA demethylation.
- Katsunori Fujiki
- , Akihiro Shinoda
- & Masayuki Murata
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miR-137 forms a regulatory loop with nuclear receptor TLX and LSD1 in neural stem cells
The microRNA miR-137 is enriched in the brain of mice and induces the differentiation of adult neural stem cells. Now, Sun and colleagues report that miR-137 negatively regulates proliferation of neurons in embryonic mice and that TLX and LSD1 cooperate to negatively regulate miR-137 expression, blocking premature differentiation.
- GuoQiang Sun
- , Peng Ye
- & Yanhong Shi
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Article
| Open Access
The nuclear orphan receptor Nr4a2 induces Foxp3 and regulates differentiation of CD4+ T cells
Regulatory T cells are characterized by the expression of Foxp3, however, how the expression of this protein is controlled is unclear. Here, the authors show that the nuclear orphan receptor, Nr4a2, is a transcriptional activator of Foxp3, and suggest that it is required for the function of regulatory T cells.
- Takashi Sekiya
- , Ikkou Kashiwagi
- & Akihiko Yoshimura
Hepatocyte FBXW7-dependent activity of nutrient-sensing nuclear receptors controls systemic energy homeostasis and NASH progression in male mice