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Nuclear receptor crosstalk can be defined as the interplay between different nuclear receptors or between their overlapping signalling pathways. A subset of nuclear receptors (such as PPARs and RARs) engage in the formation of well-characterized ‘typical’ heterodimers with RXR. ‘Atypical’ heterodimers (such as GR with PPARs, or PPAR with ERR) might form a novel class of physical complexes that might be more transient in nature. These heterodimers might harbour strong transcriptional flexibility, with no strict need for DNA binding of both partners. Direct crosstalk could stem from a pairwise physical association between atypical nuclear receptor heterodimers, either via pre-existing interaction pairs or via interactions that are newly induced with small molecules; such crosstalk might constitute an uncharted space to target nuclear receptor physiological and/or pathophysiological actions. In this Review, we discuss the emerging aspects of crosstalk in the nuclear receptor field and present various mechanistic crosstalk modes with examples that support applicability of the atypical heterodimer concept. Stabilization or disruption, in a context-dependent or cell type-dependent manner, of these more transient heterodimers is expected to fuel unprecedented translational approaches to yield novel therapeutic agents to treat major human diseases with higher precision.This Review discusses the emerging aspects of crosstalk in the nuclear receptor field. The authors present various mechanistic crosstalk modes and provide examples that support applicability of the atypical heterodimer concept.

The nuclear receptors REV-ERBα and -β link circadian rhythms and metabolism. Like other nuclear receptors, REV-ERB activity can be regulated by ligands, including naturally occurring heme. A putative ligand, SR9009, has been reported to elicit a range of beneficial effects in healthy as well as diseased animal models and cell systems. However, the direct involvement of REV-ERBs in these effects of SR9009 has not been thoroughly assessed, as experiments were not performed in the complete absence of both proteins. Here, we report the generation of a mouse model for conditional genetic deletion of REV-ERBα and -β. We show that SR9009 can decrease cell viability, rewire cellular metabolism, and alter gene transcription in hepatocytes and embryonic stem cells lacking both REV-ERBα and -β. Thus, the effects of SR9009 cannot be used solely as surrogate for REV-ERB activity.

Key Points Steroid receptors classically function in the nucleus, regulating the expression of genes that are important for a wide range of cellular functions. It has now become clear that many classic steroid receptors also localize to other cellular compartments (including, prominently, the plasma membrane) to activate various signalling pathways. Signalling from membrane-localized steroid receptors can elicit non-genomic responses, such as G protein and kinase signalling. Steroid receptor signalling from the membrane can also be involved in the regulation of gene expression, sometimes by engaging in crosstalk with nuclear pools of the respective receptor. Membrane-initiated steroid signalling has been shown to have various physiological functions and has been associated with the development and propagation of cancer. Transgenic mice that selectively express only one functional oestrogen receptor-α pool — either membrane or nuclear — display phenotypes that overlap significantly with those of mice completely lacking oestrogen receptor-α, indicating that both pools are necessary for most oestrogen-dependent processes. More broadly, it can be concluded that extranuclear steroid signalling is required for full steroid hormone action during development and organ homeostasis. Steroid hormone receptors are well known to regulate various aspects of animal physiology by acting as transcriptional regulators in the nucleus. However, it is now evident that these receptors can also be targeted to extranuclear locations (such as the plasma membrane), where they instigate rapid signals that contribute to steroid-mediated cellular responses. Steroid hormone receptors mediate numerous crucial biological processes and are classically thought to function as transcriptional regulators in the nucleus. However, it has been known for more than 50 years that steroids evoke rapid responses in many organs that cannot be explained by gene regulation. Mounting evidence indicates that most steroid receptors in fact exist in extranuclear cellular pools, including at the plasma membrane. This latter pool, when engaged by a steroid ligand, rapidly activates signals that affect various aspects of cellular biology. Research into the mechanisms of signalling instigated by extranuclear steroid receptor pools and how this extranuclear signalling is integrated with responses elicited by nuclear receptor pools provides novel understanding of steroid hormone signalling and its roles in health and disease.

Summary The role of abscisic acid (ABA) receptors, PYR1/PYL/RCAR (PYLs), is well established in ABA signalling and plant drought response, but limited research has explored the regulation of wheat PYLs in this process, especially the effects of their allelic variations on drought tolerance or grain yield. Here, we found that the overexpression of a TaABFs‐regulated PYL gene, TaPYL1‐1B, exhibited higher ABA sensitivity, photosynthetic capacity and water‐use efficiency (WUE), all contributed to higher drought tolerance than that of wild‐type plants. This heightened water‐saving mechanism further increased grain yield and protected productivity during water deficit. Candidate gene association analysis revealed that a favourable allele TaPYL1‐1BIn‐442, carrying an MYB recognition site insertion in the promoter, is targeted by TaMYB70 and confers enhanced expression of TaPYL1‐1B in drought‐tolerant genotypes. More importantly, an increase in frequency of the TaPYL1‐1BIn‐442 allele over decades among modern Chinese cultivars and its association with high thousand‐kernel weight together demonstrated that it was artificially selected during wheat improvement efforts. Taken together, our findings illuminate the role of TaPYL1‐1B plays in coordinating drought tolerance and grain yield. In particular, the allelic variant TaPYL1‐1BIn‐442 substantially contributes to enhanced drought tolerance while maintaining high yield, and thus represents a valuable genetic target for engineering drought‐tolerant wheat germplasm.

Cellular homeostasis requires the proper nuclear-cytoplasmic partitioning of large molecules, which is often deregulated in cancer. XPO1 is an export receptor responsible for the nuclear-cytoplasmic transport of hundreds of proteins and multiple RNA species. XPO1 is frequently overexpressed and/or mutated in human cancers and functions as an oncogenic driver. Suppression of XPO1-mediated nuclear export, therefore, presents a unique therapeutic strategy. In this review, we summarize the physiological functions of XPO1 as well as the development of various XPO1 inhibitors and provide an update on the recent clinical trials of the SINE compounds. We also discuss potential future research directions on the molecular function of XPO1 and the clinical application of XPO1 inhibitors.

Mitophagy, or mitochondria autophagy, plays a critical role in selective removal of damaged or unwanted mitochondria. Several protein receptors, including Atg32 in yeast, NIX/BNIP3L, BNIP3 and FUNDCI in mammalian systems, directly act in mitophagy. Atg32 interacts with Atg8 and Atgll on the surface of mitochondria, promoting core Atg protein assembly for mitophagy. NIX/BNIP3L, BNIP3 and FUNDC1 also have a classic motif to directly bind LC3 （Atg8 homolog in mammals） for activation of mitophagy. Recent studies have shown that receptor-mediated mitophagy is regulated by reversible protein phosphorylation. Casein kinase 2 （CK2） phosphorylates Atg32 and activates mitophagy in yeast. In contrast, in mammalian cells Src kinase and CK2 phosphorylate FUNDC1 to prevent mitophagy. Notably, in response to hypoxia and FCCP treatment, the mitochondrial phosphatase PGAM5 dephosphorylates FUNDC1 to activate mitophagy. Here, we mainly focus on recent advances in our understanding of the molecular mechanisms underlying the activation of receptor-mediated mitophagy and the implications of this catabolic process in health and disease.

The circadian clock regulates behavioural and physiological processes in a 24-h cycle. The nuclear receptors REV-ERBα and REV-ERBβ are involved in the cell-autonomous circadian transcriptional/translational feedback loops as transcriptional repressors. A number of studies have also demonstrated a pivotal role of REV-ERBs in regulation of metabolic, neuronal, and inflammatory functions including bile acid metabolism, lipid metabolism, and production of inflammatory cytokines. Given the multifunctional role of REV-ERBs, it is important to elucidate the mechanism through which REV-ERBs exert their functions. To this end, we established a Rev-erbα / Rev-erbβ double-knockout mouse embryonic stem (ES) cell model and analyzed the circadian clock and clock-controlled output gene expressions. A comprehensive mRNA-seq analysis revealed that the double knockout of both Rev-erbα and Rev-erbβ does not abrogate expression rhythms of E-box-regulated core clock genes but drastically changes a diverse set of other rhythmically-expressed output genes. Of note, REV-ERBα/ β deficiency does not compromise circadian expression rhythms of PER2, while REV-ERB target genes, Bmal1 and Npas2 , are significantly upregulated. This study highlight the relevance of REV-ERBs as pivotal output mediators of the mammalian circadian clock.

Key Points Members of the nuclear receptor superfamily of transcription factors have important roles in modulating the responses of macrophages, microglia and lymphocytes to pro-inflammatory signalling molecules. The nuclear receptor co-repressor (NCoR) and silencing mediator of retinoic acid and thyroid hormone receptors (SMRT) co-repressor complexes function to maintain basal repression of a subset of genes that are activated by Toll-like receptors and other pro-inflammatory signalling pathways. These co-repressor complexes must be removed in response to inflammatory signals to allow maximal gene induction. Peroxisome proliferator-activated receptor-γ (PPARγ) and liver X receptors antagonize a subset of inflammatory response genes by preventing the signal-dependent removal of NCoR and SMRT complexes. Glucocorticoid receptor antagonizes a subset of inflammatory response genes by preventing interactions of nuclear factor-κB (NF-κB) with co-activators that are required in a gene-specific manner. Glucocorticoid receptor and nuclear receptor related 1 (NURR1) antagonize a subset of inflammatory response genes by mediating the recruitment of co-repressor complexes to activator protein 1 (AP1) and NF-κB factors bound to target genes. Emerging findings in T cells indicate that nuclear receptors use a combination of activation and repression pathways to regulate the differentiation and function of distinct helper T cell subsets. This Review article describes how a subset of nuclear receptors can antagonize pro-inflammatory gene expression, through transrepression mechanisms in macrophages and microglia, and regulate the differentiation and activation of inflammatory helper T cells, particularly T helper 17 cells. Members of the nuclear receptor superfamily of ligand-dependent transcription factors regulate diverse aspects of immunity and inflammation by both positively and negatively regulating gene expression. Here, we review recent studies providing insights into the distinct mechanisms that enable nuclear receptors to antagonize pro-inflammatory programmes of gene expression in macrophages and T cells by altering the turnover or recruitment of co-repressors and co-activators in a gene-specific manner. These nuclear receptor-dependent transrepression pathways are proposed to have roles in controlling the initiation, magnitude and duration of pro-inflammatory gene expression and are amenable to pharmacological manipulation.

Key Points Bile acids are amphipathic steroids derived from cholesterol that serve important physiological functions such as bile formation and intestinal fat absorption that are dependent on their detergent nature The discovery of farnesoid X receptor (FXR) and G-protein coupled bile acid receptor 1 (TGR5) as bile acid receptors that regulate glucose, lipid and energy metabolism has highlighted bile acids as key players in metabolic control Modulators of bile acid receptors have been developed as potential treatments for cholestatic liver diseases and metabolic diseases; organ-specific and/or gene-cluster-selective modulators are expected in the near future Type 2 diabetes mellitus (T2DM) is accompanied by a shift in primary bile acid synthesis towards cholic acid and a corresponding increase in the secondary bile acid deoxycholic acid Beneficial effects of bile acid sequestrants on glucose metabolism in patients with T2DM could reflect changed compartmentalization of the bile acid pool that modifies intestinal bile acid signalling In this article, Kuipers and colleagues review how bile acids modulate glucose and lipid metabolism. The authors discuss the mechanisms by which bile acids, agonists of bile acid signalling pathways and bile acid sequestrants influence glucose levels in animal models and patients with insulin resistance and type 2 diabetes mellitus and how altered bile acid metabolism might contribute to the beneficial effects of bariatric surgery. Over the past decade, it has become apparent that bile acids are involved in a host of activities beyond their classic functions in bile formation and fat absorption. The identification of the farnesoid X receptor (FXR) as a nuclear receptor directly activated by bile acids and the discovery that bile acids are also ligands for the membrane-bound, G-protein coupled bile acid receptor 1 (also known as TGR5) have opened new avenues of research. Both FXR and TGR5 regulate various elements of glucose, lipid and energy metabolism. Consequently, a picture has emerged of bile acids acting as modulators of (postprandial) metabolism. Therefore, strategies that interfere with either bile acid metabolism or signalling cascades mediated by bile acids may represent novel therapeutic approaches for metabolic diseases. Synthetic modulators of FXR have been designed and tested, primarily in animal models. Furthermore, the use of bile acid sequestrants to reduce plasma cholesterol levels has unexpected benefits. For example, treatment of patients with type 2 diabetes mellitus (T2DM) with sequestrants causes substantial reductions in plasma levels of glucose and HbA 1c . This Review aims to provide an overview of the molecular mechanisms by which bile acids modulate glucose and energy metabolism, particularly focusing on the glucose-lowering actions of bile acid sequestrants in insulin resistant states and T2DM.

Nuclear receptors (NRs) are ligand-dependent transcription factors required for liver development and function. As a consequence, NRs have emerged as attractive drug targets in a wide range of liver diseases. However, liver dysfunction and failure are linked to loss of hepatocyte identity characterised by deficient NR expression and activities. This might at least partly explain why several pharmacological NR modulators have proven insufficiently efficient to improve liver functionality in advanced stages of diseases such as metabolic dysfunction-associated steatotic liver disease (MASLD). In this perspective, we review the most recent advances in the hepatic NR field and discuss the contribution of multiomic approaches to our understanding of their role in the molecular organisation of an intricated transcriptional regulatory network, as well as in liver intercellular dialogues and interorgan cross-talks. We discuss the potential benefit of novel therapeutic approaches simultaneously targeting multiple NRs, which would not only reactivate the hepatic NR network and restore hepatocyte identity but also impact intercellular and interorgan interplays whose importance to control liver functions is further defined. Finally, we highlight the need of considering individual parameters such as sex and disease stage in the development of NR-based clinical strategies.