SKN-1 Activity Research Articles

Quinic acid protects against the development of Huntington’s disease in Caenorhabditis elegans model

BackgroundQuinic acid (QA), a cyclitol and cyclohexanecarboxylic acid, is a natural product that is present and can be isolated from edible herbals like tea, coffee and several fruits and vegetables. It was previously reported that QA exerted antioxidant and neuroprotective activity against dementia. However, it was not tested for its neuroprotective potential against Huntington’s disease (HD). Since aging related disorders are greatly linked to oxidative stress conditions, we focused on testing the oxidative stress resistant activity and protective effect of QA against the development of HD by using the multicellular Caenorhabditis elegans (C. elegans) worm model.MethodsFirstly, QA was tested for its oxidative stress resistant properties. In survival assay, wild type and mutant skn-1 and daf-16 worms were exposed to oxidative stress conditions by using H2O2. Activation of SKN-1 pathway and expression of its downstream genes gcs-1 and gst-4 were also tested. Secondly, the effect of QA was evaluated on HD by testing its ability to decrease the formation of polyQ150 aggregates. Furthermore, its effect on the accumulation of polyglutamine (polyQ35 and polyQ40 aggregates) was tested.ResultsHere we report that QA could improve the survival of C. elegans after exposure to oxidative stress caused by H2O2 while also exerting antioxidant effects through the activation of SKN-1/Nrf2 pathway. Moreover, QA could be a potential candidate to protect against HD due to its effects on decreasing the formation of polyQ150, polyQ35 and polyQ40 aggregates.ConclusionsThis study highlights the importance of QA as a natural compound in defending against oxidative stress and the development of neurodegenerative diseases like HD.

β-asarone protects against age-related motor decline via activation of SKN-1/Nrf2 and subsequent induction of GST-4

Decelerating motor decline is important for promoting healthy aging in the elderly population. Acorus tatarinowii Schott is a traditional Chinese medicine that contains β-asarone as a pharmacologically active constituent. We found that β-asarone can decelerate motor decline in various age groups of Caenorhabditis elegans, while concurrently prolonging their lifespan and modulating synaptic transmission. To understand the mechanisms of its efficacy in motor improvement, we investigated and discovered that mitochondrial fragmentation, a marker for aging, is delayed after β-asarone treatment. Moreover, their efficacy is blocked by dysfunctional mitochondria. Corresponding to their role in regulating mitochondrial homeostasis, we found that SKN-1/Nrf2 and GST-4 are critical in the β-asarone treatment, and they appear to be activated via the insulin/IGF-1 signaling pathway. Well-developed intestinal microvilli are required for this process. Our study demonstrates the efficacy and mechanism of β-asarone treatment in age-related motor decline, contributing to the discovery of drugs for achieving healthy aging.

Serotonin deficiency from constitutive SKN-1 activation drives pathogen apathy

When an organism encounters a pathogen, the host innate immune system activates to defend against pathogen colonization and toxic xenobiotics produced. C. elegans employ multiple defense systems to ensure survival when exposed to Pseudomonas aeruginosa including activation of the cytoprotective transcription factor SKN-1/NRF2. Although wildtype C. elegans quickly learn to avoid pathogens, here we describe a peculiar apathy-like behavior towards PA14 in animals with constitutive activation of SKN-1, whereby animals choose not to leave and continue to feed on the pathogen even when a non-pathogenic and healthspan-promoting food option is available. Although lacking the urgency to escape the infectious environment, animals with constitutive SKN-1 activity are not oblivious to the presence of the pathogen and display the typical pathogen-induced intestinal distension and eventual demise. SKN-1 activation, specifically in neurons and intestinal tissues, orchestrates a unique transcriptional program which leads to defects in serotonin signaling that is required from both neurons and non-neuronal tissues. Serotonin depletion from SKN-1 activation limits pathogen defenses capacity, drives the pathogen-associated apathy behaviors and induces a synthetic sensitivity to selective serotonin reuptake inhibitors. Taken together, our work reveals interesting insights into how animals perceive environmental pathogens and subsequently alter behavior and cellular programs to promote survival.

Activated SKN-1 alters the aging trajectories of long-lived C. elegans mutants.

In the presence of stressful environments, the SKN-1 cytoprotective transcription factor is activated to induce the expression of gene targets that can restore homeostasis. However, chronic activation of SKN-1 results in diminished health and a reduction of lifespan. Here we demonstrate the necessity of modulating SKN-1 activity to maintain the longevity-promoting effects associated with genetic mutations that impair daf-2/insulin receptor signaling, the eat-2 model of caloric restriction, and glp-1-dependent loss of germ cell proliferation. A hallmark of animals with constitutive SKN-1 activation is the age-dependent loss of somatic lipids and this phenotype is linked to a general reduction in survival in animals harboring the skn-1gf allele, but surprisingly, daf-2lf; skn-1gf double mutant animals do not redistribute somatic lipids which suggests the insulin signaling pathway functions downstream of SKN-1 in the maintenance of lipid distribution. As expected, the eat-2lf allele, which independently activates SKN-1, continues to display somatic lipid depletion in older ages with and without the skn-1gf activating mutation. In contrast, the presence of the skn-1gf allele does not lead to somatic lipid redistribution in glp-1lf animals that lack a proliferating germline. Taken together, these studies support a genetic model where SKN-1 activity is an important regulator of lipid mobilization in response to nutrient availability that fuels the developing germline by engaging the daf-2/insulin receptor pathway.

Disrupting the SKN-1 homeostat: mechanistic insights and phenotypic outcomes.

The mechanisms that govern maintenance of cellular homeostasis are crucial to the lifespan and healthspan of all living systems. As an organism ages, there is a gradual decline in cellular homeostasis that leads to senescence and death. As an organism lives into advanced age, the cells within will attempt to abate age-related decline by enhancing the activity of cellular stress pathways. The regulation of cellular stress responses by transcription factors SKN-1/Nrf2 is a well characterized pathway in which cellular stress, particularly xenobiotic stress, is abated by SKN-1/Nrf2-mediated transcriptional activation of the Phase II detoxification pathway. However, SKN-1/Nrf2 also regulates a multitude of other processes including development, pathogenic stress responses, proteostasis, and lipid metabolism. While this process is typically tightly regulated, constitutive activation of SKN-1/Nrf2 is detrimental to organismal health, this raises interesting questions surrounding the tradeoff between SKN-1/Nrf2 cryoprotection and cellular health and the ability of cells to deactivate stress response pathways post stress. Recent work has determined that transcriptional programs of SKN-1 can be redirected or suppressed to abate negative health outcomes of constitutive activation. Here we will detail the mechanisms by which SKN-1 is controlled, which are important for our understanding of SKN-1/Nrf2 cytoprotection across the lifespan.

PATHOGEN APATHY RESULTING FROM SKN-1 ACTIVATION: A MARK OF RESILIENCE OR A RATTLED GUT FEELING?

Abstract Innate immunity is a key driver in promoting survival against xenobiotic stressors and hostile environments and an appropriate immune response is essential to organismal health across lifespan. Caenorhabditis elegans encounter pathogens in their natural environment and initiate cytoprotective and immune responses that can have long-lasting effects on health, even after the pathogen has been neutralized. Pseudomonas aeruginosa (PA14) is an opportunistic pathogen that is lethal to C. elegans with prolonged exposure. C. elegans employ multiple defense mechanisms to ensure survival upon exposure to pathogens to defend against the current infection and to avoid continued exposure, including activation of the key cytoprotective transcription factor SKN-1 (mammalian homologue Nrf2). Although wild type C. elegans quickly learn to avoid pathogens, our current work documents a peculiar apathy to pathogen in animals with constitutive activation of SKN-1. The outcome is surprising as the role of SKN-1 is to protect an animal from intracellular and environmental insults. This behavior is mediated by tissue specific actions of SKN-1 that initiate cell non-autonomous responses for pathogen avoidance, survival, and metabolic adaptation. Based on transcriptional signature of animals with SKN-1 activation upon exposure to PA14 we observed that the apathy behavior is independent of somatic lipid depletion, thus uncoupling these two exceptional physiological responses. Further, we define the role of neurosignalling molecules in the gut-brain axis that drive the apathy response to pathogens. Our work reveals new insights into how animals perceive pathogens in the environment and subsequently alter behavior and cellular programs to promote survival.

A dicer-related helicase opposes the age-related pathology from SKN-1 activation in ASI neurons.

Coordination of cellular responses to stress is 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 Caenorhabditis 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 noncoding RNA, define a molecular signature of animals with constitutive SKN-1 activation and diminished healthspan. We reveal neddylation as a unique 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 nonautonomous circuit to maintain organism-level homeostasis in response to excessive SKN-1 transcriptional activity in the sensory nervous system.

Comparative analysis of the molecular and physiological consequences of constitutive SKN-1 activation.

Molecular homeostats play essential roles across all levels of biological organization to ensure a return to normal function after responding to abnormal internal and environmental events. SKN-1 is an evolutionarily conserved cytoprotective transcription factor that is integral for the maintenance of cellular homeostasis upon exposure to a variety of stress conditions. Despite the essentiality of turning on SKN-1/NRF2 in response to exogenous and endogenous stress, animals with chronic activation of SKN-1 display premature loss of health with age, and ultimately, diminished lifespan. Previous genetic models of constitutive SKN-1 activation include gain-of-function alleles of skn-1 and loss-of-function alleles of wdr-23 that impede the turnover of SKN-1 by the ubiquitin proteasome. Here, we define a novel gain-of-function mutation in the xrep-4 locus that results in constitutive activation of SKN-1 in the absence of stress. Although each of these genetic mutations results in continuously unregulated transcriptional output from SKN-1, the physiological consequences of each model on development, stress resistance, reproduction, lipid homeostasis, and lifespan are distinct. Here, we provide a comprehensive assessment of the differential healthspan impacts across multiple models of constitutive SKN-1 activation. Although our results reveal the universal need to reign in the uncontrolled activity of cytoprotective transcription factors, we also define the unique signatures of each model of constitutive SKN-1 activation, which provides innovative solutions for the design of molecular "off-switches" of unregulated transcriptional homeostats.

Geniposide-Rich Gardenia jasminoides Ellis Fruit Extract Increases Healthspan in Caenorhabditis elegans.

The human life span has been markedly extended since the 1900s, but it has not brought healthy aging to everyone. This increase in life expectancy without an increase in healthspan is a major global concern that imposes considerable health care budgets and degrades the quality of life of older adults. Dietary interventions are a promising strategy to increase healthspan. In this study, we evaluated whether a Gardenia jasminoides Ellis fruit ethanol extract (GFE) increases the life span of Caenorhabditis elegans (C.elegans). Treatment with 10mg/mL GFE increased the life span by 27.1% when compared to the vehicle group. GFE (10mg/mL) treatment improved healthspan-related markers (pharyngeal pumping, muscle quality, age-pigment, and reactive oxygen species accumulation) and exerted a protective effect against amyloid β 1-42 toxicity. These effects of GFE are related to the inhibition of insulin/IGF-1 signaling and activation of SKN-1/Nrf, thereby promoting the expression of stress resistance-related genes. In addition, treatment with 10mM geniposide, the most abundant component of GFE, improved healthspan-related markers and increased life span by 18.55% when compared to the vehicle group. Collectively, these findings demonstrate that GFE and its component geniposide increase the life span along with healthspan in C.elegans.

The metabolite alpha-ketobutyrate extends lifespan by promoting peroxisomal function in C. elegans

Metabolism is intimately linked to aging. There is a growing number of studies showing that endogenous metabolites may delay aging and improve healthspan. Through the analysis of existing transcriptome data, we discover a link between activation of the transsulfuration pathway and a transcriptional program involved in peroxisome function and biogenesis in long-lived glp-1(e2141ts) mutant Caenorhabditis elegans worms. Subsequently, we show that supplementation with α-ketobutyrate, an intermediate of the transsulfuration pathway, extends lifespan in wild-type worms. Alpha-ketobutyrate augments the production of NAD+ via the lactate dehydrogenase LDH-1, leading to SIR-2.1/SIRT1-mediated enhanced peroxisome function and biogenesis, along with a concomitant increase in the expression of acox-1.2/ACOX1 in the peroxisomal fatty acid β-oxidation pathway. ACOX-1.2/ACOX1 promotes H2O2 formation, thereby resulting in activation of SKN-1/NRF2. This transcription factor in turn extends the lifespan of worms by driving expression of autophagic and lysosomal genes. Finally, we show that α-ketobutyrate also delays the cellular senescence in fibroblast cells through the SIRT1-ACOX1-H2O2-NRF2 pathway. This finding uncovers a previously unknown role for α-ketobutyrate in organismal lifespan and healthspan by coordinating the NAD+-SIRT1 signaling and peroxisomal function.

MEKK-3 Acts Cooperatively with NSY-1 in SKN-1-Dependent Manner against Oxidative Stress and Aging in Caenorhabditis elegans.

Simple SummaryOxidative stress has been linked to myriad pathologies and aging. Here, we show that MEKK-3- and NSY-1-mediated nuclear translocation of SKN-1 is critical for protection against oxidative stress and for longevity in Caenorhabditis elegans. A genetic approach revealed that the knockdown of MEKK-3 and NSY-1, components of the p38 MAPK pathway, significantly reduced the resistance to oxidative stress achieved by SKN-1 overexpression. Mechanistic analyses showed that MEKK-3 and NSY-1 participate in the accumulation of SKN-1 in intestinal nuclei, which is required for the activation of phase II detoxification genes. These results provide molecular insights into oxidative stress resistance and reveal potential targets for aging-associated diseases.Oxidative stress resulting from reactive oxygen species and other toxic metabolites is involved in human diseases, and it plays an important role in aging. In Caenorhabditis elegans, SKN-1 is required for protection against oxidative stress and aging. As p38 mitogen-activated protein kinase signaling is activated in response to oxidative stress, SKN-1 accumulates in intestinal nuclei and induces phase II detoxification genes. However, NSY-1, a well-known mitogen-activated protein kinase kinase kinase (MAPKKK) of C. elegans, acts as a partial regulator of the SKN-1-induced oxidative stress signaling pathway, suggesting that the regulator for optimal activation of SKN-1 remains unknown. Here, we report a MAPKKK, MEKK-3, as a new regulator required for full activation of SKN-1-mediated resistance against oxidative stress and aging. In RNA-interference-based screening, we found that the simultaneous knockdown of mekk-3 and nsy-1 significantly decreased the oxidative stress resistance and survival of SKN-1 transgenic worms. MEKK-3 was induced in response to oxidative stress. Mechanistic analysis revealed that double knockdown of mekk-3 and nsy-1 completely suppressed the nuclear localization of SKN-1. These results were reproduced in mutant worms in which SKN-1 is constitutively localized to intestinal nuclei. In addition, mekk-3 and nsy-1 were required for optimal induction of SKN-1 target genes such as gcs-1 and trx-1. These data indicate that MEKK-3 plays an essential role in the SKN-1-dependent signaling pathway involved in oxidative stress resistance and longevity by cooperating with NSY-1.

Neurotoxicity Evaluation of Nanomaterials Using C. elegans: Survival, Locomotion Behaviors, and Oxidative Stress.

Nanomaterials are broadly used in a variety of industries and consumer products. However, studies have demonstrated that many nanomaterials, including metal-containing nanoparticles and nanoplastics, have neurotoxic effects. Caenorhabditis elegans (C. elegans) is a widely used model organism with numerous advantages for research, including transparency, short life span, well-characterized nervous system, complete connectome, available genome, and numerous genetic tools. C. elegans has been extensively used to assess the neurotoxicity of multiple chemicals via survival assays, behavioral tests, neuronal morphology studies, and various molecular and mechanistic analyses. However, detailed protocols describing general assays in C. elegans to examine the neurotoxic effects of nanomaterials are limited. Here, we describe protocols for assessing nanomaterial neurotoxicity in C. elegans. We describe the steps for exposure and subsequent evaluation of survival, locomotion behavior, and oxidative stress. Survival and locomotion behavior are measured in wild-type N2 strains to assess acute neurotoxicity. Oxidative stress is used as an endpoint here since it is one of the most predominant and common changes induced by nanomaterials. VP596 nematodes, which express GFP upon activation of skn-1 (the worm homolog of Nrf2), are evaluated for assays of oxidative stress in response to test nanomaterials. These assays can be readily used to quickly examine the neurotoxicity of nanomaterials in vivo, laying the foundation for mechanistic studies of nanomaterials and their impacts on health and physiology. © 2022 Wiley Periodicals LLC. Basic Protocol 1: Exposure of C. elegans to nanomaterials Basic Protocol 2: Survival assessment Basic Protocol 3: Assessment of locomotion behavior Basic Protocol 4: Analysis of oxidative stress.

SKN-1 regulates stress resistance downstream of amino catabolism pathways

SummaryThe deleterious potential to generate oxidative stress is a fundamental challenge to metabolism. The oxidative stress response transcription factor, SKN-1/NRF2, can sense and respond to changes in metabolic state, although the mechanism and consequences of this remain unknown. Here, we performed a genetic screen in C. elegans targeting amino acid catabolism and identified multiple metabolic pathways as regulators of SKN-1 activity. We found that knockdown of the conserved amidohydrolase T12A2.1/amdh-1 activates a unique subset of SKN-1 regulated genes. Interestingly, this transcriptional program is independent of canonical P38-MAPK signaling components but requires ELT-3, NHR-49 and MDT-15. This activation of SKN-1 is dependent on upstream histidine catabolism genes HALY-1 and Y51H4A.7/UROC-1 and may occur through accumulation of a catabolite, 4-imidazolone-5-propanoate. Activating SKN-1 results in increased oxidative stress resistance but decreased survival to heat stress. Together, our data suggest that SKN-1 acts downstream of key catabolic pathways to influence physiology and stress resistance.

Streblus asper Lour. exerts MAPK and SKN-1 mediated anti-aging, anti-photoaging activities and imparts neuroprotection by ameliorating Aβ in Caenorhabditis elegans

BACKGROUND: Streblus asper Lour., has been reported to have anti-aging and neuroprotective efficacies in vitro. OBJECTIVE: To analyze the anti-aging, anti-photoaging and neuroprotective efficacies of S. asper in Caenorhabditis elegans. METHODS: C. elegans (wild type and gene specific mutants) were treated with S. asper extract and analyzed for lifespan and other health benefits through physiological assays, fluorescence microscopy, qPCR and Western blot. RESULTS: The plant extract was found to increase the lifespan, reduce the accumulation of lipofuscin and modulate the expression of candidate genes. It could extend the lifespan of both daf-16 and daf-2 mutants whereas the pmk-1 mutant showed no effect. The activation of skn-1 was observed in skn-1::GFP transgenic strain and in qPCR expression. Further, the extract can extend the lifespan of UV-A exposed nematodes along with reducing ROS levels. Additionally, the extract also extends lifespan and reduces paralysis in Aβ transgenic strain, apart from reducing Aβ expression. CONCLUSIONS: S. asper was able to extend the lifespan and healthspan of C. elegans which was independent of DAF-16 pathway but dependent on SKN-1 and MAPK which could play a vital role in eliciting the anti-aging, anti-photoaging and neuroprotective effects, as the extract could impart oxidative stress resistance and neuroprotection.

Tribbles pseudokinase NIPI-3 regulates intestinal immunity in Caenorhabditis elegans by controlling SKN-1/Nrf activity.

In Caenorhabditis elegans, ROS generated in response to intestinal infection induces SKN-1, a protective transcription factor homologous to nuclear factor erythroid 2-related factor 1 or 2 (NRF1/2) in mammals. Many factors regulate SKN-1, including the p38 mitogen-activated protein kinase (MAPK) cascade that activates SKN-1 by phosphorylation. In this work, another positive regulator of SKN-1 is identified: NIPI-3, a Tribbles pseudokinase. NIPI-3 has been reported to protect against intestinal infection by negatively regulating the CCAT enhancer binding protein (C/EBP) bZIP transcription factor CEBP-1. Here we demonstrate that CEBP-1 positively regulates the vhp-1 transcript, which encodes a phosphatase that dephosphorylates the p38 MAPK called PMK-1. The increased levels of VHP-1 caused by CEBP-1 transcriptional enhancement result in less PMK-1 phosphorylation, affecting SKN-1 activity and intestinal resistance to the pathogen. Thedata support a model in which NIPI-3's negative regulation of CEBP-1 decreases VHP-1 phosphatase activity, allowing increased stimulation of SKN-1 activity by the p38 MAPK phosphorylation cascade in the intestine.

Mitochondrial hydrogen peroxide positively regulates neuropeptide secretion during diet-induced activation of the oxidative stress response

Mitochondria play a pivotal role in the generation of signals coupling metabolism with neurotransmitter release, but a role for mitochondrial-produced ROS in regulating neurosecretion has not been described. Here we show that endogenously produced hydrogen peroxide originating from axonal mitochondria (mtH2O2) functions as a signaling cue to selectively regulate the secretion of a FMRFamide-related neuropeptide (FLP-1) from a pair of interneurons (AIY) in C. elegans. We show that pharmacological or genetic manipulations that increase mtH2O2 levels lead to increased FLP-1 secretion that is dependent upon ROS dismutation, mitochondrial calcium influx, and cysteine sulfenylation of the calcium-independent PKC family member PKC-1. mtH2O2-induced FLP-1 secretion activates the oxidative stress response transcription factor SKN-1/Nrf2 in distal tissues and protects animals from ROS-mediated toxicity. mtH2O2 levels in AIY neurons, FLP-1 secretion and SKN-1 activity are rapidly and reversibly regulated by exposing animals to different bacterial food sources. These results reveal a previously unreported role for mtH2O2 in linking diet-induced changes in mitochondrial homeostasis with neuropeptide secretion.

SUMO promotes longevity and maintains mitochondrial homeostasis during ageing in Caenorhabditis elegans

The insulin/IGF signalling pathway impacts lifespan across distant taxa, by controlling the activity of nodal transcription factors. In the nematode Caenorhabditis elegans, the transcription regulators DAF-16/FOXO and SKN-1/Nrf function to promote longevity under conditions of low insulin/IGF signalling and stress. The activity and subcellular localization of both DAF-16 and SKN-1 is further modulated by specific posttranslational modifications, such as phosphorylation and ubiquitination. Here, we show that ageing elicits a marked increase of SUMO levels in C. elegans. In turn, SUMO fine-tunes DAF-16 and SKN-1 activity in specific C. elegans somatic tissues, to enhance stress resistance. SUMOylation of DAF-16 modulates mitochondrial homeostasis by interfering with mitochondrial dynamics and mitophagy. Our findings reveal that SUMO is an important determinant of lifespan, and provide novel insight, relevant to the complexity of the signalling mechanisms that influence gene expression to govern organismal survival in metazoans.

Nickel-Induced Developmental Neurotoxicity in C. elegans Includes Cholinergic, Dopaminergic and GABAergic Degeneration, Altered Behaviour, and Increased SKN-1 Activity.

Nickel (Ni) is a ubiquitous metal in the environment with increasing industrial application. While environmental and occupational exposure to Ni compounds has been known to result in toxicities to several organs, including the liver, kidney, lungs, skin and gonads, neurotoxic effects have not been extensively investigated. In this present study, we investigated specific neuronal susceptibility in a C. elegans model of acute Ni neurotoxicity. Wild-type worms and worms expressing green fluorescent protein (GFP) in either cholinergic, dopaminergic or GABAergic neurons were treated with NiCl2 for 1h at the first larval (L1) stage. The median lethal dose (LD50) was calculated to be 5.88mM in this paradigm. Morphology studies of GFP-expressing worms showed significantly increasing degeneration of cholinergic, dopaminergic and GABAergic neurons with increasing Ni concentration. Significant functional changes in locomotion and basal slowing response assays reflected that cholinergic and dopaminergic neuronal function, respectively, were impaired due to Ni treatment. Interestingly, a small but significant number of worms exhibited shrinker phenotype upon Ni exposure but no loopy head foraging behaviour was observed suggesting that function of D-type GABAergic neurons of C elegans may be specifically attenuated while the RME subset of GABAergic neurons are not. GFP expression due to induction of glutathione S-transferase 4 (gst-4), a target of Nrf2 homolog skn-1, was increased in a Pgst-4::GFP worm highlighting Ni-induced oxidative stress. RT-qPCR verified upregulation of this expression of gst-4 immediately after exposure. These data suggest that oxidative stress is associated with neuronal damage and altered behaviour due to developmental Ni exposure.

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

Early host responses toward pathogens are essential for defense against infection. In Caenorhabditis elegans, the transcription factor, SKN-1, regulates cellular defenses during xenobiotic intoxication and bacterial infection. However, constitutive activation of SKN-1 results in pleiotropic outcomes, including a redistribution of somatic lipids to the germline, which impairs health and shortens lifespan. Here, we show that exposing C. elegans to Pseudomonas aeruginosa similarly drives the rapid depletion of somatic, but not germline, lipid stores. Modulating the epigenetic landscape refines SKN-1 activity away from innate immunity targets, which alleviates negative metabolic outcomes. Similarly, exposure to oxidative stress redirects SKN-1 activity away from pathogen response genes while restoring somatic lipid distribution. In addition, activating p38/MAPK signaling in the absence of pathogens, is sufficient to drive SKN-1-dependent loss of somatic fat. These data define a SKN-1- and p38-dependent axis for coordinating pathogen responses, lipid homeostasis, and survival and identify transcriptional redirection, rather than inactivation, as a mechanism for counteracting the pleiotropic consequences of aberrant transcriptional activity.

A Novel Mechanism To Prevent H2S Toxicity in Caenorhabditis elegans.

Hydrogen sulfide (H2S) is an endogenously produced signaling molecule that can be cytoprotective, especially in conditions of ischemia/reperfusion injury. However, H2S is also toxic, and unregulated accumulation or exposure to environmental H2S can be lethal. In Caenorhabditis elegans, the hypoxia inducible factor (hif-1) coordinates the initial transcriptional response to H2S, and is essential to survive exposure to low concentrations of H2S. We performed a forward genetic screen to identify mutations that suppress the lethality of hif-1 mutant animals in H2S. The mutations we recovered are specific for H2S, as they do not suppress embryonic lethality or reproductive arrest of hif-1 mutant animals in hypoxia, nor can they prevent the death of hif-1 mutant animals exposed to hydrogen cyanide. The majority of hif-1 suppressor mutations we recovered activate the skn-1/Nrf2 transcription factor. Activation of SKN-1 by hif-1 suppressor mutations increased the expression of a subset of H2S-responsive genes, consistent with previous findings that skn-1 plays a role in the transcriptional response to H2S. Using transgenic rescue, we show that overexpression of a single gene, rhy-1, is sufficient to protect hif-1 mutant animals in H2S. The rhy-1 gene encodes a predicated O-acyltransferase enzyme that has previously been shown to negatively regulate HIF-1 activity. Our data indicate that RHY-1 has novel, hif-1 independent, function that promotes survival in H2S.