Cholesterol Regulates Innate Immunity via Nuclear Hormone Receptor NHR-8
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ABSTRACT:
SUBMITTER: Otarigho B
PROVIDER: S-EPMC8571716 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Cholesterol is an essential nutrient for the function of diverse biological processes and for steroid biosynthesis across metazoans. However, the role of cholesterol in immune function remains understudied. Using the nematode Caenorhabditis elegans, which depends on the external environment for cholesterol, we studied the relationship between cholesterol and innate immunity. We found that the transporter CHUP-1 is required for the effect of cholesterol in the development of innate immunity and that the cholesterol-mediated immune response requires the nuclear hormone receptor NHR-8. Cholesterol acts through NHR-8 to transcriptionally regulate immune genes that are controlled by conserved immune pathways, including a p38/PMK-1 MAPK pathway, a DAF-2/DAF-16 insulin pathway, and an Nrf/SKN-1 pathway. Our results indicate that cholesterol plays a key role in the activation of conserved microbicidal pathways that are essential for survival against bacterial infections.
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Project description:Hormone-gated nuclear receptors (NRs) are conserved transcriptional regulators of metabolism, reproduction, and homeostasis. Here we show that C. elegans NHR-8 NR, a homolog of vertebrate liver X and vitamin D receptors, regulates nematode cholesterol balance, fatty acid desaturation, apolipoprotein production, and bile acid metabolism. Loss of nhr-8 results in a deficiency in bile acid-like steroids, called the dafachronic acids, which regulate the related DAF-12/NR, thus controlling entry into the long-lived dauer stage through cholesterol availability. Cholesterol supplementation rescues various nhr-8 phenotypes, including developmental arrest, unsaturated fatty acid deficiency, reduced fertility, and shortened life span. Notably, nhr-8 also interacts with daf-16/FOXO to regulate steady-state cholesterol levels and is synthetically lethal in combination with insulin signaling mutants that promote unregulated growth. Our studies provide important insights into nuclear receptor control of cholesterol balance and metabolism and their impact on development, reproduction, and aging in the context of larger endocrine networks.
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Project description:Nuclear hormone receptors (NHRs) are ligand-gated transcription factors that control adaptive host responses following recognition of specific endogenous or exogenous ligands. Although NHRs have expanded dramatically in C. elegans compared to other metazoans, the biological function of only a few of these genes has been characterized in detail. Here, we demonstrate that an NHR can activate an anti-pathogen transcriptional program. Using genetic epistasis experiments, transcriptome profiling analyses and chromatin immunoprecipitation-sequencing, we show that, in the presence of an immunostimulatory small molecule, NHR-86 binds to the promoters of immune effectors to activate their transcription. NHR-86 is not required for resistance to the bacterial pathogen Pseudomonas aeruginosa at baseline, but activation of NHR-86 by this compound drives a transcriptional program that provides protection against this pathogen. Interestingly, NHR-86 targets immune effectors whose basal regulation requires the canonical p38 MAPK PMK-1 immune pathway. However, NHR-86 functions independently of PMK-1 and modulates the transcription of these infection response genes directly. These findings characterize a new transcriptional regulator in C. elegans that can induce a protective host response towards a bacterial pathogen.
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Project description:Mammalian nuclear hormone receptors (NHRs), such as liver X receptor, farnesoid X receptor, and peroxisome proliferator-activated receptors (PPARs), precisely control energy metabolism. Consequently, these receptors are important targets for the treatment of metabolic diseases, including diabetes and obesity. A thorough understanding of NHR fat regulatory networks has been limited, however, by a lack of genetically tractable experimental systems. Here we show that deletion of the Caenorhabditis elegans NHR gene nhr-49 yielded worms with elevated fat content and shortened life span. Employing a quantitative RT-PCR screen, we found that nhr-49 influenced the expression of 13 genes involved in energy metabolism. Indeed, nhr-49 served as a key regulator of fat usage, modulating pathways that control the consumption of fat and maintain a normal balance of fatty acid saturation. We found that the two phenotypes of the nhr-49 knockout were linked to distinct pathways and were separable: The high-fat phenotype was due to reduced expression of enzymes in fatty acid beta-oxidation, and the shortened adult life span resulted from impaired expression of a stearoyl-CoA desaturase. Despite its sequence relationship with the mammalian hepatocyte nuclear factor 4 receptor, the biological activities of nhr-49 were most similar to those of the mammalian PPARs, implying an evolutionarily conserved role for NHRs in modulating fat consumption and composition. Our findings in C. elegans provide novel insights into how NHR regulatory networks are coordinated to govern fat metabolism.
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Project description:Nuclear hormone receptors (NHRs) are transcription factors that regulate numerous physiological and developmental processes and represent important drug targets. NHR-49, an ortholog of Hepatocyte Nuclear Factor 4 (HNF4), has emerged as a key regulator of lipid metabolism and life span in the nematode worm Caenorhabditis elegans. However, many aspects of NHR-49 function remain poorly understood, including whether and how it regulates individual sets of target genes and whether its activity is modulated by a ligand. A recent study identified three gain-of-function (gof) missense mutations in nhr-49 (nhr-49(et7), nhr-49(et8), and nhr-49(et13), respectively). These substitutions all affect the ligand-binding domain (LBD), which is critical for ligand binding and protein interactions. Thus, these alleles provide an opportunity to test how three specific residues contribute to NHR-49 dependent gene regulation. We used computational and molecular methods to delineate how these mutations alter NHR-49 activity. We find that despite originating from a screen favoring the activation of specific NHR-49 targets, all three gof alleles cause broad upregulation of NHR-49 regulated genes. Interestingly, nhr-49(et7) and nhr-49(et8) exclusively affect nhr-49 dependent activation, whereas the nhr-49(et13) surprisingly affects both nhr-49 mediated activation and repression, implicating the affected residue as dually important. We also observed phenotypic non-equivalence of these alleles, as they unexpectedly caused a long, short, and normal life span, respectively. Mechanistically, the gof substitutions altered neither protein interactions with the repressive partner NHR-66 and the coactivator MDT-15 nor the subcellular localization or expression of NHR-49. However, in silico structural modeling revealed that NHR-49 likely interacts with small molecule ligands and that the missense mutations might alter ligand binding, providing a possible explanation for increased NHR-49 activity. In sum, our findings indicate that the three nhr-49 gof alleles are non-equivalent, and highlight the conserved V411 residue affected by et13 as critical for gene activation and repression alike.
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Project description:The ability to sense and respond to proteotoxic insults declines with age, leaving cells vulnerable to chronic and acute stressors. Reproductive cues modulate this decline in cellular proteostasis to influence organismal stress resilience in C. elegans. We previously uncovered a pathway that links the integrity of developing embryos to somatic health in reproductive adults. Here, we show that the nuclear receptor NHR-49, a functional homolog of mammalian peroxisome proliferator-activated receptor alpha (PPARα), regulates stress resilience and proteostasis downstream of embryo integrity and other pathways that influence lipid homeostasis, and upstream of HSF-1. Disruption of the vitelline layer of the embryo envelope, which activates a proteostasis-enhancing inter-tissue pathway in somatic tissues, also triggers changes in lipid catabolism gene expression that are accompanied by an increase in fat stores. NHR-49 together with its co-activator MDT-15 contributes to this remodeling of lipid metabolism and is also important for the elevated stress resilience mediated by inhibition of the embryonic vitelline layer as well as by other pathways known to change lipid homeostasis, including reduced insulin-like signaling and fasting. Further, we show that increased NHR-49 activity is sufficient to suppress polyglutamine aggregation and improve stress resilience in an HSF-1-dependent manner. Together, our results establish NHR-49 as a key regulator that links lipid homeostasis and cellular resilience to proteotoxic stress.
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Project description:Aging and immunity are inextricably linked and many genes that extend life span also enhance immunoresistance. However, it remains unclear whether longevity-enhancing factors modulate immunity and longevity by discrete or shared mechanisms. Here, we demonstrate that the Caenorhabditis elegans pro-longevity factor, NHR-49, also promotes resistance against Pseudomonas aeruginosa but modulates immunity and longevity distinctly. NHR-49 expression increases upon germline ablation, an intervention that extends life span, but was lowered by Pseudomonas infection. The immunosusceptibility induced by nhr-49 loss of function was rescued by neuronal NHR-49 alone, whereas the longevity diminution was rescued by expression in multiple somatic tissues. The well-established NHR-49 target genes, acs-2 and fmo-2, were also differentially regulated following germline elimination or Pseudomonas exposure. Interestingly, neither gene conferred immunity toward Gram-negative Pseudomonas, unlike their known functions against gram-positive pathogens. Instead, genes encoding antimicrobial factors and xenobiotic-response proteins upregulated by NHR-49 contributed to resistance against Pseudomonas. Thus, NHR-49 is differentially regulated by interventions that bring about long-term changes (life span extension) versus short-term stress (pathogen exposure) and in response it orchestrates discrete outputs, including pathogen-specific transcriptional programs.
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Project description:This SuperSeries is composed of the SubSeries listed below. Keywords: Expression profiling by high throughput sequencing
2019-01-09 | GSE117724 | GEO
Project description:Plants employ cell-surface pattern recognition receptors (PRRs) to detect pathogens. Although phytohormones produced during PRR signaling play an essential role in innate immunity, a direct link between PRR activation and hormone regulation is unknown. EFR is a PRR that recognizes bacterial EF-Tu and activates immune signaling. Here we report that EFR regulates the phytohormone jasmonic acid (JA) through direct phosphorylation of a receptor-like cytoplasmic kinase, BIK1. The BIK1 structure revealed that the EFR-phosphorylated sites reside on a uniquely extended loop away from the BIK1 kinase core domain. Phosphomimetic mutations of these sites resulted in increased phytohormones and enhanced resistance to bacterial infections. In addition to its documented plasma membrane localization, BIK1 also localizes to the nucleus and interacts directly with WRKY transcription factors involved in the JA and salicylic acid (SA) regulation. These findings demonstrate the mechanistic basis of signal transduction from PRR to phytohormones, mediated through a PRR-BIK1-WRKY axis.
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Project description:Pregnane X receptor (PXR) is a member of nuclear receptor superfamily and responsible for the detoxification of xenobiotics. Our previously study demonstrated that PXR is expressed in endothelial cells (ECs) and acts as a master regulator of detoxification genes to protect ECs against xenobiotics. Vascular endothelial cells are key sentinel cells to sense the pathogens and xenobiotics. In this study, we examined the potential function of PXR in the regulation of innate immunity in vasculatures. Treatments with PXR agonists or overexpression of a constitutively active PXR in cultured ECs increased gene expression of the key pattern recognition receptors, including Toll-like receptors (TLR-2, -4, -9) and NOD-like receptors (NOD-1 and -2 and NLRP3). In particular, PXR agonism triggered the activation of NLRP3 inflammasome and the ensuing cleavage and maturation of caspase-1 and interleukin-1β (IL-1β). Conversely, selective antagonism or gene silencing of PXR abrogated NLRP3 inflammasome activation. In addition, we identified NLRP3 as a transcriptional target of PXR by using the promoter-reporter and ChIP assays. In summary, our findings revealed a novel regulatory mechanism of innate immune by PXR, which may act as a master transcription factor controlling the convergence between the detoxification of xenobiotics and the innate immunity against them.
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