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Transcriptional redirection of activated SKN-1/NRF2 abates the negative metabolic outcomes of a perceived pathogen infection

ABSTRACT: Optimal health requires perpetual transcriptional fidelity of gene expression. SKN-1/NRF2 is a cytoprotective transcription factor in C. elegans that regulates the expression of cellular defenses during stress, including: nutrient deprivation, redox imbalance, and xenobiotic and pathogen exposure. Constitutive activation of SKN-1 results in pleiotropic outcomes, including shortened lifespan and protective redistribution of somatic fat to the germline. We measured lipid distribution between the soma and germ tissues after manipulation of SKN-1 activity. Modulating the epigenetic landscape refines SKN-1 activity away from innate immunity targets and alleviates negative metabolic outcomes. Similarly, paraquat exposure redirects SKN-1 activity toward oxidative stress responses and away from pathogen response genes, which restores lipid distribution across tissues. Lastly, activating p38 MAPK signaling is sufficient to drive SKN-1-dependent loss of somatic fat. These data reveal a coordination of organismal metabolic homeostasis with pathogen responses and identifies mechanisms for counteracting the pleiotropic consequences of aberrant transcriptional activity.

ORGANISM(S): Caenorhabditis elegans

PROVIDER: GSE123531 | GEO | 2019/10/15

REPOSITORIES: GEO

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Transcriptional redirection of activated SKN-1/NRF2 abates the negative metabolic outcomes of a perceived pathogen infection

Project description:Transcriptional redirection of activated SKN-1/NRF2 abates the negative metabolic outcomes of a perceived pathogen infection

| PRJNA509132 | ENA

Project description:Coordination of cellular responses to stress are essential for health across the lifespan. The transcription factor SKN-1 is an essential homeostat that mediates survival in stress-inducing environments and cellular dysfunction, but constitutive activation of SKN-1 drives premature aging thus revealing the importance of turning off cytoprotective pathways. Here we identify how SKN-1 activation in two ciliated ASI neurons in C. elegans results in an increase in organismal transcriptional capacity that drives pleiotropic outcomes in peripheral tissues. An increase in the expression of established SKN-1 stress response and lipid metabolism gene classes of RNA in the ASI neurons, in addition to the increased expression of several classes of non-coding RNA, define a molecular signature of animals with constitutive SKN-1 activation and diminished healthspan. We reveal neddylation as a novel regulator of the SKN-1 homeostat that mediates SKN-1 abundance within intestinal cells. Moreover, RNAi-independent activity of the dicer-related DExD/H-box helicase, drh-1, in the intestine, can oppose the effects of aberrant SKN-1 transcriptional activation and delays age-dependent decline in health. Taken together, our results uncover a cell non-autonomous circuit to maintain organism-level homeostasis in response to excessive SKN-1 transcriptional activity in the sensory nervous system.

2023-12-06 | GSE246466 | GEO

2023-12-06 | GSE246465 | GEO

RNA-seq analysis of germline stem cell removal and loss of SKN-1 in C. elegans

Project description:In C. elegans, ablation of germline stem cells (GSCs) extends lifespan, but also increases fat accumulation and alters lipid metabolism, raising the intriguing question of how these effects might be related. Here we show that a lack of GSCs results in a broad transcriptional reprogramming, in which the conserved detoxification regulator SKN-1/Nrf increases stress resistance, proteasome activity, and longevity. SKN-1 also activates diverse lipid metabolism genes and reduces fat storage, thereby alleviating the increased fat accumulation caused by GSC absence. Surprisingly, SKN-1 is activated by signals from this fat, which appears to derive from unconsumed yolk that was produced for reproduction. We conclude that SKN-1 plays a direct role in maintaining lipid homeostasis, in which it is activated by lipids. This SKN-1 function may explain the importance of mammalian Nrf proteins in fatty liver disease, and suggests that particular endogenous or dietary lipids might promote health through SKN-1/Nrf.

2015-07-21 | GSE63075 | GEO

Skn-1-deficient effect on the gastrocnemius

Project description:Analysis of gastrocnemius from male wild type(WT) and Skn-1-deficient mice. Skn-1-deficient mice have reduced body weight with low body fat due to increased energy expenditure. Results provide insight into the molecular mechanisms up-regulating metabolism.

2017-02-11 | GSE76936 | GEO

Loss of mitochondrial proline catabolism depletes FAD, impairing sperm function, and male reproductive advantage

Project description:Exposure to environmental stress has a clinically established influence on male reproductive health, but the impact of normal cellular metabolism on sperm quality and function is less well-defined. Here we show that homeostatic changes in mitochondrial dynamics driven by defective mitochondrial proline catabolism result in pleiotropic consequences on sperm quality and competitive fitness. Disruption of alh-6, which converts 1-pyrroline-5-carboxylate (P5C) to glutamate, results in P5C accumulation that drives oxidative stress, activation of the cytoprotective transcription factor SKN-1, and a reduction of energy-storing flavin adenine dinucleotide (FAD) levels. These molecular changes lead to premature male reproductive senescence by reducing sperm quality. These sperm-specific defects are suppressed by abating P5C metabolism, by treatment with antioxidants to combat reactive oxygen species (ROS), or by feeding diets that restore FAD levels. Our results define a role for mitochondrial proline catabolism and FAD homeostasis on sperm function and specify strategies to pharmacologically reverse unintended outcomes from SKN-1/Nrf transcriptional activation.

2020-02-17 | GSE121920 | GEO

A PTEN variant uncouples longevity from impaired fitness in C. elegans via tuning the activity of FOXO and NRF

Project description:Insulin/IGF-1 signaling (IIS) regulates various physiological aspects in many species. In C. elegans, mutations in daf-2/insulin/IGF-1 receptor dramatically increase lifespan and pathogen resistance, but generally impair motility, development, and reproduction. Whether these pleiotropic effects can be dissociated at a specific step in the IIS pathway remains unknown. Here we show that a single amino acid change in DAF-18, PTEN phosphatase, allows worms to maintain longevity and enhanced immunity in daf-2 mutants compared to wild-type, without defects in growth and motility. Through performing a mutagenesis screen, we identified a missense mutation in daf-18 [daf-18(yh1)], which suppressed developmental defects in daf-2 mutants with small effects on pathogen resistance. We showed that the daf-18(yh1) caused a reduction in its function, but maintained long lifespan, motility span, and resistance against various stresses in daf-2 mutants. We further showed that daf-18(yh1) retained the activity of DAF-16/FOXO but restricted detrimental upregulation of SKN-1/NRF, for exerting beneficial physiological consequences. Our study will provide important insights into how one evolutionarily conserved component, PTEN coordinates healthy longevity and fitness.

2021-08-13 | GSE154338 | GEO

Redirection of SKN-1 abates the negative metabolic outcomes of a perceived pathogen infection.

Project description: Not available

| S-EPMC6825279 | biostudies-literature

TRX-1 Regulates SKN-1 Nuclear Localization Cell Non-Autonomously in Caenorhabditis elegans

Project description:The Caenorhabditis elegans oxidative stress response transcription factor, SKN-1, is essential for the maintenance of redox homeostasis and is a functional ortholog of the Nrf family of transcription factors. The numerous levels of regulation that govern these transcription factors underscore their importance. Here, we add a thioredoxin, encoded by trx-1, to the expansive list of SKN-1 regulators. We report that loss of trx-1 promotes nuclear localization of intestinal SKN-1 in a redox-independent, cell non-autonomous fashion from the ASJ neurons. Furthermore, this regulation is not general to the thioredoxin family, as two other C. elegans thioredoxins TRX-2 and TRX-3 do not play a role in this process. Moreover, TRX-1-dependent regulation requires signaling from the p38 MAPK signaling pathway. However, while TRX-1 regulates SKN-1 nuclear localization, SKN-1 transcriptional activity remains largely unaffected. Interestingly, RNA-Seq revealed that loss of trx-1 elicits a general, organism-wide down-regulation of several classes of genes; those encoding for collagens and lipid transport and localization being most prevalent. However, one prominent lipase-related gene, lips-6, is highly up regulated upon loss of trx-1 in a skn-1-dependent manner. Together, these results uncover a novel role for a thioredoxin in regulating intestinal SKN-1 nuclear localization in a cell non-autonomous manner, thereby contributing to the understanding of the processes involved in maintaining redox homeostasis throughout an organism. Four samples were analyzed: Two nematode strains were analyzed, each under non-stressed and stressed (10mM NaAs) conditions

2016-04-01 | E-GEOD-77976 | biostudies-arrayexpress

TRX-1 Regulates SKN-1 Nuclear Localization Cell Non-Autonomously in Caenorhabditis elegans

2016-04-01 | GSE77976 | GEO

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