Bacterial pattern recognition in C. elegans by the nuclear hormone receptor NHR-86/HNF4
Ontology highlight
ABSTRACT:
ORGANISM(S): Caenorhabditis elegans
PROVIDER: GSE202258 | GEO | 2023/02/07
REPOSITORIES: GEO
Similar Datasets
Project description:Germline-encoded pattern recognition receptors (e.g. Toll-like receptors) play key roles in innate immune activation. However, some metazoans, such as C. elegans, do not have canonical mechanisms of pattern recognition, yet they are able to mount anti-pathogen immune defenses. Here, we demonstrate that a nuclear hormone receptor (NHR), a ligand-gated transcription factor, functions in immune activation and pathogen defense. NHRs have expanded dramatically in C. elegans compared to other metazoans. Because NHRs often function redundantly, it has been challenging experimentally to characterize the biology of individual NHRs. Here, we use genetic epistasis experiments, transcriptome profiling analyses and chromatin immunoprecipitation to show NHR-86 is sufficient to activate protective immune defenses against the bacterial pathogen Pseudomonas aeruginosa. Interestingly, NHR-86 drives the transcription of immune effectors whose basal regulation requires the canonical p38 MAPK PMK-1 immune pathway. However, NHR-86 functions independently of PMK-1 and directly induces the transcription of infection response genes in a manner that confers protection from bacterial infection. Importantly, we found that nhr-86 does control immune gene expression and is necessary for host defense against a different pathogen, Enterococcus faecalis. Our findings characterize an ancient role of an NHR in innate immunity, and suggest that the expansion of the NHR protein family in C. elegans has been fueled in part by the need to activate immune defenses in response to pathogen attack.
2019-01-09 | GSE117719 | GEO
Project description:Germline-encoded pattern recognition receptors (e.g. Toll-like receptors) play key roles in innate immune activation. However, some metazoans, such as C. elegans, do not have canonical mechanisms of pattern recognition, yet they are able to mount anti-pathogen immune defenses. Here, we demonstrate that a nuclear hormone receptor (NHR), a ligand-gated transcription factor, functions in immune activation and pathogen defense. NHRs have expanded dramatically in C. elegans compared to other metazoans. Because NHRs often function redundantly, it has been challenging experimentally to characterize the biology of individual NHRs. Here, we use genetic epistasis experiments, transcriptome profiling analyses and chromatin immunoprecipitation to show NHR-86 is sufficient to activate protective immune defenses against the bacterial pathogen Pseudomonas aeruginosa. Interestingly, NHR-86 drives the transcription of immune effectors whose basal regulation requires the canonical p38 MAPK PMK-1 immune pathway. However, NHR-86 functions independently of PMK-1 and directly induces the transcription of infection response genes in a manner that confers protection from bacterial infection. Importantly, we found that nhr-86 does control immune gene expression and is necessary for host defense against a different pathogen, Enterococcus faecalis. Our findings characterize an ancient role of an NHR in innate immunity, and suggest that the expansion of the NHR protein family in C. elegans has been fueled in part by the need to activate immune defenses in response to pathogen attack.
2019-01-09 | GSE117700 | GEO
Project description:Endogenous and exogenous stresses elicit transcriptional responses that limit damage and promote cell/organismal survival. Like its mammalian counterparts, Hepatocyte Nuclear Factor 4 (HNF4) and peroxisome proliferator-activated receptor a (PPARa), Caenorhabditis elegans NHR-49 is a well-established regulator of lipid metabolism. Here, we reveal that NHR-49 is essential to activate a transcriptional response common to organic peroxide and fasting, which includes the pro-longevity gene fmo-2/flavin-containing monoxygenase. These NHR-49-dependent, stress-responsive genes are also upregulated in long-lived glp-1/notch receptor mutants, and two of them contribute to increased oxidative stress resistance in wild-type worms and long-lived glp-1 mutants. Similar to its role in lipid metabolism, NHR-49 requires the Mediator subunit mdt-15 to promote stress-induced gene expression. However, NHR-49 acts independently from the transcription factor hlh-30/TFEB that also promotes fmo-2 expression. Similarly, activation of the p38 MAPK, PMK-1, which is important for adaptation to a variety of stresses, is only important for peroxide-induced expression of a subset of NHR-49-dependent genes, including fmo-2. Notably, we find that organic peroxide increases NHR-49 protein levels, apparently by a post-transcriptional mechanism that does not require PMK-1 activation. Together these findings establish a new role for the HNF4/PPARa-related NHR-49 as a stress-activated regulator of cytoprotective gene expression.
2018-03-05 | GSE107799 | GEO
Project description:Animals can thrive on variable food resources as a result of autonomous processes and beneficial relationships with their gut microbes. Food intake elicits major physiological changes, which are compensated with transient systemic responses that maintain homeostasis in the organism. This integration of external information occurs through cellular sensory elements, such as nuclear receptors, which modulate gene expression in response to specific cues. Given the importance of the germline stem cells (GSCs) for the development of the germ line and the continuity of the species, it is reasonable to assume that GSCs might be shielded from the negative influence of environmental perturbations. To our knowledge, however, there are no mechanisms reported that protect proliferating germ cells from harmful dietary metabolites. Using Caenorhabditis elegans as a model, we report that the somatic activity of the conserved nuclear receptor nhr-114/HNF4 protects GSC divisions and GSC integrity from dietary metabolites. In the absence of nhr-114 and on certain bacterial diets, otherwise somatically normal animals accumulate germ cell division defects during development and become sterile. We find that in nhr-114(-) animals the induction of germline defects and sterility depends on the bacterial metabolic status with respect to the essential amino acid tryptophan. This illustrates an animal-microbe interaction in which somatic nuclear receptor activity preserves the germline by buffering against dietary metabolites, likely through a somatic detoxifying response. Overall, our findings uncover an unprecedented and presumably evolutionary conserved soma-to-germline axis of communication that maintains reproductive robustness on variable food resources. Trasncriptional profiles of adult sterile nhr-114(RNAi) animals were compared to those of sterile glp-1(q224ts) animals. Independently, the transcriptional profiles of wild type animals fed an OP50 diet supplemented with Tryptophan was compared to wild type animals fed a standard OP50 diet.
2013-03-01 | E-GEOD-43864 | biostudies-arrayexpress
Project description:Sphingolipids are required for diverse biological functions and are degraded by specific catabolic enzymes. However, the mechanisms that regulate sphingolipid catabolism are not known. Here we characterize a transcriptional axis that regulates sphingolipid breakdown to control resistance against bacterial infection. From an RNAi screen for transcriptional regulators of pathogen resistance in the nematode C. elegans, we identified the nuclear hormone receptor nhr-66, a ligand-gated transcription factor homologous to human hepatocyte nuclear factor 4. Tandem chromatin immunoprecipitation-sequencing (ChIP-seq) and RNA sequencing (RNA-seq) experiments revealed that NHR-66 is a transcriptional repressor, which directly targets sphingolipid catabolism genes. Transcriptional de-repression of two sphingolipid catabolic enzymes in nhr-66 loss-of-function mutants drives the breakdown of sphingolipids, which enhances host susceptibility to infection with the bacterial pathogen Pseudomonas aeruginosa. These data define transcriptional control of sphingolipid catabolism in the regulation of cellular sphingolipids, a process that is necessary for pathogen resistance.
2023-09-08 | GSE240426 | GEO
Project description:Sphingolipids are required for diverse biological functions and are degraded by specific catabolic enzymes. However, the mechanisms that regulate sphingolipid catabolism are not known. Here we characterize a transcriptional axis that regulates sphingolipid breakdown to control resistance against bacterial infection. From an RNAi screen for transcriptional regulators of pathogen resistance in the nematode C. elegans, we identified the nuclear hormone receptor nhr-66, a ligand-gated transcription factor homologous to human hepatocyte nuclear factor 4. Tandem chromatin immunoprecipitation-sequencing (ChIP-seq) and RNA sequencing (RNA-seq) experiments revealed that NHR-66 is a transcriptional repressor, which directly targets sphingolipid catabolism genes. Transcriptional de-repression of two sphingolipid catabolic enzymes in nhr-66 loss-of-function mutants drives the breakdown of sphingolipids, which enhances host susceptibility to infection with the bacterial pathogen Pseudomonas aeruginosa. These data define transcriptional control of sphingolipid catabolism in the regulation of cellular sphingolipids, a process that is necessary for pathogen resistance.
2023-09-08 | GSE240425 | GEO
Project description:The nematode Caenorhabditis elegans offers currently untapped potential for carrying out high-throughput, live-animal screens of low molecular weight compound libraries to identify molecules that target a variety of cellular processes. We previously used a bacterial infection assay in C. elegans to identify 119 compounds that affect host-microbe interactions among 37,214 tested. We subsequently found that one of these small molecules, RPW-24, protects C. elegans from bacterial infection by stimulating the host immune response of the nematode. Using transcriptome profiling, epistasis pathway analyses with C. elegans mutants, and an RNAi screen, we showed that RPW-24 promotes resistance to Pseudomonas aeruginosa infection by inducing the transcription of a remarkably small number of C. elegans genes (~1.3% of all genes) in a manner that partially depends on the evolutionarily-conserved p38 MAP kinase pathway and the transcription factor ATF-7. These data demonstrated that the immunostimulatory activity of RPW-24 is required for its efficacy and define a novel C. elegans-based strategy to identify compounds with activity against antibiotic-resistant bacterial pathogens. Here we present the microarray data that were used to define the genes that are differentially regulated in wild-type nematodes following exposure to RPW-24.
2012-04-14 | GSE37266 | GEO
Project description:The nematode Caenorhabditis elegans offers currently untapped potential for carrying out high-throughput, live-animal screens of low molecular weight compound libraries to identify molecules that target a variety of cellular processes. We previously used a bacterial infection assay in C. elegans to identify 119 compounds that affect host-microbe interactions among 37,214 tested. We subsequently found that one of these small molecules, RPW-24, protects C. elegans from bacterial infection by stimulating the host immune response of the nematode. Using transcriptome profiling, epistasis pathway analyses with C. elegans mutants, and an RNAi screen, we showed that RPW-24 promotes resistance to Pseudomonas aeruginosa infection by inducing the transcription of a remarkably small number of C. elegans genes (~1.3% of all genes) in a manner that partially depends on the evolutionarily-conserved p38 MAP kinase pathway and the transcription factor ATF-7. These data demonstrated that the immunostimulatory activity of RPW-24 is required for its efficacy and define a novel C. elegans-based strategy to identify compounds with activity against antibiotic-resistant bacterial pathogens. Here we present the microarray data that were used to define the genes that are differentially regulated in wild-type nematodes following exposure to RPW-24.
2012-04-14 | GSE37266 | GEO
Project description:Animals can thrive on variable food resources as a result of autonomous processes and beneficial relationships with their gut microbes. Food intake elicits major physiological changes, which are compensated with transient systemic responses that maintain homeostasis in the organism. This integration of external information occurs through cellular sensory elements, such as nuclear receptors, which modulate gene expression in response to specific cues. Given the importance of the germline stem cells (GSCs) for the development of the germ line and the continuity of the species, it is reasonable to assume that GSCs might be shielded from the negative influence of environmental perturbations. To our knowledge, however, there are no mechanisms reported that protect proliferating germ cells from harmful dietary metabolites. Using Caenorhabditis elegans as a model, we report that the somatic activity of the conserved nuclear receptor nhr-114/HNF4 protects GSC divisions and GSC integrity from dietary metabolites. In the absence of nhr-114 and on certain bacterial diets, otherwise somatically normal animals accumulate germ cell division defects during development and become sterile. We find that in nhr-114(-) animals the induction of germline defects and sterility depends on the bacterial metabolic status with respect to the essential amino acid tryptophan. This illustrates an animal-microbe interaction in which somatic nuclear receptor activity preserves the germline by buffering against dietary metabolites, likely through a somatic detoxifying response. Overall, our findings uncover an unprecedented and presumably evolutionary conserved soma-to-germline axis of communication that maintains reproductive robustness on variable food resources.
2013-03-01 | GSE43864 | GEO
Project description:Animals can thrive on variable food resources as a result of autonomous processes and beneficial relationships with their gut microbes. Food intake elicits major physiological changes, which are compensated with transient systemic responses that maintain homeostasis in the organism. This integration of external information occurs through cellular sensory elements, such as nuclear receptors, which modulate gene expression in response to specific cues. Given the importance of the germline stem cells (GSCs) for the development of the germ line and the continuity of the species, it is reasonable to assume that GSCs might be shielded from the negative influence of environmental perturbations. To our knowledge, however, there are no mechanisms reported that protect proliferating germ cells from harmful dietary metabolites. Using Caenorhabditis elegans as a model, we report that the somatic activity of the conserved nuclear receptor nhr-114/HNF4 protects GSC divisions and GSC integrity from dietary metabolites. In the absence of nhr-114 and on certain bacterial diets, otherwise somatically normal animals accumulate germ cell division defects during development and become sterile. We find that in nhr-114(-) animals the induction of germline defects and sterility depends on the bacterial metabolic status with respect to the essential amino acid tryptophan. This illustrates an animal-microbe interaction in which somatic nuclear receptor activity preserves the germline by buffering against dietary metabolites, likely through a somatic detoxifying response. Overall, our findings uncover an unprecedented and presumably evolutionary conserved soma-to-germline axis of communication that maintains reproductive robustness on variable food resources.
2013-03-01 | GSE43864 | GEO