SKN-1 regulates stress resistance downstream of amino catabolism pathways.
Ontology highlight
ABSTRACT:
SUBMITTER: Frankino PA
PROVIDER: S-EPMC9240870 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:RIPK1 is a crucial regulator of cell death and survival. Ripk1 deficiency promotes mouse survival in the prenatal period while inhibits survival in the early postnatal period without a clear mechanism. Metabolism regulation and autophagy are critical to neonatal survival from severe starvation at birth. However, the mechanism by which RIPK1 regulates starvation resistance and survival remains unclear. Here, we address this question by discovering the metabolic regulatory role of RIPK1. First, metabolomics analysis reveals that Ripk1 deficiency specifically increases aspartate levels in both mouse neonates and mammalian cells under starvation conditions. Increased aspartate in Ripk1-/- cells enhances the TCA flux and ATP production. The energy imbalance causes defective autophagy induction by inhibiting the AMPK/ULK1 pathway. Transcriptional analyses demonstrate that Ripk1-/- deficiency downregulates gene expression in aspartate catabolism by inactivating SP1. To summarize, this study reveals that RIPK1 serves as a metabolic regulator responsible for starvation resistance.
| S-EPMC8536712 | biostudies-literature
Project description:Caenorhabditis elegans NRF (NF-E2-related factor)/CNC (Cap'n'collar) transcription factor, Skinhead-1 (SKN-1), is conservatively critical for promoting phase II detoxification gene expressions in response to oxidative stress. SKN-1 activity is controlled by well-known phosphorylation and recently-reported O-GlcNAcylation. Whether other kinds of posttanslational modifications of SKN-1 occur and influence its function remains elusive. Here, we found arginines 484 and 516 (R484/R516) of SKN-1 were asymmetrically dimethylated by PRMT-1. Oxidative stress enhanced the binding of PRMT-1 to SKN-1. Consequently, asymmetrical dimethylation of arginines on SKN-1 was elevated. Loss of prmt-1 or disruption of R484/R516 dimethylation decreased the enrichment of SKN-1 on the promoters of SKN-1-driven phase II detoxification genes, including gamma-glutamine cysteine synthetase gcs-1, glutathione S-transferases gst-7 and gst-4, which resulted in reduced ability of worms to defense against oxidative stress. These findings have important implications for investigating the physiological and pathological functions of arginine methylation on conserved NRF/CNC transcription factors in human diseases related to oxidative stress response.
| S-EPMC6351272 | biostudies-literature
Project description:The Nrf family of transcription factors plays a critical role in mediating adaptive responses to cellular stress and defends against neurodegeneration, aging, and cancer. Here, we report a novel role for the Caenorhabditis elegans Nrf homolog SKN-1 in regulating synaptic transmission at neuromuscular junctions (NMJs). Activation of SKN-1, either by acute pharmacological treatment with the mitochondrial toxin sodium arsenite or by mutations that cause constitutive SKN-1 activation, results in defects in neuromuscular function. Additionally, elimination of the conserved WD40 repeat protein WDR-23, a principal negative regulator of SKN-1, results in impaired locomotion and synaptic vesicle and neuropeptide release from cholinergic motor axons. Mutations that abolish skn-1 activity restore normal neuromuscular function to wdr-23 mutants and animals treated with toxin. We show that negative regulation of SKN-1 by WDR-23 in the intestine, but not at neuromuscular junctions, is necessary and sufficient for proper neuromuscular function. WDR-23 isoforms differentially localize to the outer membranes of mitochondria and to nuclei, and the effects of WDR-23 on neuromuscular function are dependent on its interaction with cullin E3 ubiquitin ligase. Finally, whole-transcriptome RNA sequencing of wdr-23 mutants reveals an increase in the expression of known SKN-1/Nrf2-regulated stress-response genes, as well as neurotransmission genes not previously implicated in SKN-1/Nrf2 responses. Together, our results indicate that SKN-1/Nrf2 activation may be a mechanism through which cellular stress, detected in one tissue, affects cellular function of a distal tissue through endocrine signaling. These results provide insight into how SKN-1/Nrf2 might protect the nervous system from damage in response to oxidative stress.
| S-EPMC3605294 | biostudies-literature
Project description:In C. elegans, the transcription factor skinhead-1 (SKN-1), the ortholog of human NF-E2-related factor 2 (Nrf-2), plays important roles in oxidative stress defense and aging processes. It has been documented that the activity of SKN-1 is regulated by its phosphorylation modification. However, whether other posttranslational modifications of SKN-1 affect its function remains unclear to date. Here we report, for the first time, that SKN-1 is O-GlcNAcylated at Ser470 and Thr493 by O-GlcNActransferase OGT-1. By generating the double mutations of Ser470/Thr493 in the wild type and skn-1(zu67) worms, respectively, we found that disruption of O-GlcNAc modification on SKN-1 repressed the accumulation of SKN-1 in the intestinal nuclei, and decreased the activities of SKN-1 in modulating lifespan and oxidative stress resistance. Moreover, under oxidative stress, SKN-1 was highly O-GlcNAcylated, resulting in the decrease of GSK-3-mediated phosphorylation at Ser483 adjacent to the O-GlcNAcylated residues (Ser470 and Thr493). These data suggest that O-GlcNAcylation of SKN-1 is crucial for regulating lifespan and oxidative stress resistance via the crosstalk with its phosphorylation in C. elegans. These findings have important implications for studying the functions of O-GlcNAcylation on Nrf-2 in human aging-related diseases.
| S-EPMC5341102 | biostudies-literature
Project description:Microalgal lipid, a feasible substrate for biofuel, is typically accumulated during the stationary growth phase. Generating strains which trigger lipogenesis from the exponential growth phase will enhance lipid productivity, reduce cost of biofuel production. We characterized a lipid-rich microalgal mutant, Dunaliella tertiolecta, which exhibited a six-fold enhancement of neutral lipids production in the exponential growth phase with marginal compromise on growth (4%). Using transcriptomics and metabolomics, regulatory mechanisms of the mutant were uncovered.
2016-10-24 | GSE82121 | GEO
Project description:Trastuzumab is a successful rationally designed ERBB2-targeted therapy. However, about half of individuals with ERBB2-overexpressing breast cancer do not respond to trastuzumab-based therapies, owing to various resistance mechanisms. Clinically applicable regimens for overcoming trastuzumab resistance of different mechanisms are not yet available. We show that the nonreceptor tyrosine kinase c-SRC (SRC) is a key modulator of trastuzumab response and a common node downstream of multiple trastuzumab resistance pathways. We find that SRC is activated in both acquired and de novo trastuzumab-resistant cells and uncover a novel mechanism of SRC regulation involving dephosphorylation by PTEN. Increased SRC activation conferred considerable trastuzumab resistance in breast cancer cells and correlated with trastuzumab resistance in patients. Targeting SRC in combination with trastuzumab sensitized multiple lines of trastuzumab-resistant cells to trastuzumab and eliminated trastuzumab-resistant tumors in vivo, suggesting the potential clinical application of this strategy to overcome trastuzumab resistance.
| S-EPMC3877934 | biostudies-literature
Project description:NF-E2-related factor 2 (NRF2) transcription factor has a fundamental role in cell homeostasis maintenance as one of the master regulators of oxidative and electrophilic stress responses. Previous studies have shown that a regulatory connection exists between NRF2 and autophagy during reactive oxygen species-generated oxidative stress. The aim of the present study was to investigate how autophagy is turned off during prolonged oxidative stress, to avoid overeating and destruction of essential cellular components. AMPK is a key cellular energy sensor highly conserved in eukaryotic organisms, and it has an essential role in autophagy activation at various stress events. Here the role of human AMPK and its Caenorhabditis elegans counterpart AAK-2 was explored upon oxidative stress. We investigated the regulatory connection between NRF2 and AMPK during oxidative stress induced by tert-butyl hydroperoxide (TBHP) in HEK293T cells and C. elegans. Putative conserved NRF2/protein skinhead-1 binding sites were found in AMPK/aak-2 genes by in silico analysis and were later confirmed experimentally by using EMSA. After addition of TBHP, NRF2 and AMPK showed a quick activation; AMPK was later down-regulated, however, while NRF2 level remained high. Autophagosome formation and Unc-51-like autophagy activating kinase 1 phosphorylation were initially stimulated, but they returned to basal values after 4 h of TBHP treatment. The silencing of NRF2 resulted in a constant activation of AMPK leading to hyperactivation of autophagy during oxidative stress. We observed the same effects in C. elegans demonstrating the conservation of this self-defense mechanism to save cells from hyperactivated autophagy upon prolonged oxidative stress. We conclude that NRF2 negatively regulates autophagy through delayed down-regulation of the expression of AMPK upon prolonged oxidative stress. This regulatory connection between NRF2 and AMPK may have an important role in understanding how autophagy is regulated in chronic human morbidities characterized by oxidative stress, such as neurodegenerative diseases, certain cancer types, and in metabolic diseases.-Kosztelnik, M., Kurucz, A., Papp, D., Jones, E., Sigmond, T., Barna, J., Traka, M. H., Lorincz, T., Szarka, A., Banhegyi, G., Vellai, T., Korcsmaros, T., Kapuy, O. Suppression of AMPK/aak-2 by NRF2/SKN-1 down-regulates autophagy during prolonged oxidative stress.
| S-EPMC6338645 | biostudies-literature
Project description:The transcription factor SKN-1, the C . elegans ortholog of mammalian Nrf protein, is a well-known longevity factor, and its activation is observed in several long-lived models. SKN-1 also plays essential roles in xenobiotic and oxidative stress responses. Here, we report deleterious functions of SKN-1 in somatic stress resistance that may impair lifespan. Constitutive SKN-1 activation impairs animal resistance to several stresses, including heat, ER stress and mitochondrial stress, which result from the suppression of DAF-16, another master regulator of longevity. SKN-1 activation abrogates DAF-16 nuclear import and downregulates DAF-16 target genes under stress conditions, while SKN-1 inhibition promotes the expression of DAF-16 targets, even in long-lived mutants. Further, SKN-1 activation induces the expression of vitellogenin proteins, which are required for SKN-1-mediated suppression of DAF-16 and stress resistance. Together, these findings identify detrimental roles for SKN-1 activation in animal health, and more importantly, inspire the rethinking of the complex roles for SKN-1 in aging regulation.
| S-EPMC7202003 | biostudies-literature
Project description:Mechanisms that coordinate different metabolic pathways, such as glucose and lipid, have been recognized. However, a potential interaction between amino acid and lipid metabolism remains largely elusive. Here we show that during starvation of Caenorhabditis elegans, proline catabolism is coupled with lipid metabolism by SKN-1. Mutation of alh-6, a conserved proline catabolic enzyme, accelerates fat mobilization, enhances the expression of genes involved in fatty acid oxidation and reduces survival in response to fasting. This metabolic coordination is mediated by the activation of the transcription factor SKN-1/Nrf2, possibly due to the accumulation of the alh-6 substrate P5C, and also requires the transcriptional co-regulator MDT-15. Constitutive activation of SKN-1 induces a similar transcriptional response, which protects animals from fat accumulation when fed a high carbohydrate diet. In human cells, an orthologous alh-6 enzyme, ALDH4A1, is also linked to the activity of Nrf2, the human orthologue of SKN-1, and regulates the expression of lipid metabolic genes. Our findings identify a link between proline catabolism and lipid metabolism, and uncover a physiological role for SKN-1 in metabolism.
| S-EPMC4205844 | biostudies-other
Project description:ObjectiveGlucagon is well known to regulate blood glucose but may be equally important for amino acid metabolism. Plasma levels of amino acids are regulated by glucagon-dependent mechanism(s), while amino acids stimulate glucagon secretion from alpha cells, completing the recently described liver-alpha cell axis. The mechanisms underlying the cycle and the possible impact of hepatic steatosis are unclear.MethodsWe assessed amino acid clearance in vivo in mice treated with a glucagon receptor antagonist (GRA), transgenic mice with 95% reduction in alpha cells, and mice with hepatic steatosis. In addition, we evaluated urea formation in primary hepatocytes from ob/ob mice and humans, and we studied acute metabolic effects of glucagon in perfused rat livers. We also performed RNA sequencing on livers from glucagon receptor knock-out mice and mice with hepatic steatosis. Finally, we measured individual plasma amino acids and glucagon in healthy controls and in two independent cohorts of patients with biopsy-verified non-alcoholic fatty liver disease (NAFLD).ResultsAmino acid clearance was reduced in mice treated with GRA and mice lacking endogenous glucagon (loss of alpha cells) concomitantly with reduced production of urea. Glucagon administration markedly changed the secretion of rat liver metabolites and within minutes increased urea formation in mice, in perfused rat liver, and in primary human hepatocytes. Transcriptomic analyses revealed that three genes responsible for amino acid catabolism (Cps1, Slc7a2, and Slc38a2) were downregulated both in mice with hepatic steatosis and in mice with deletion of the glucagon receptor. Cultured ob/ob hepatocytes produced less urea upon stimulation with mixed amino acids, and amino acid clearance was lower in mice with hepatic steatosis. Glucagon-induced ureagenesis was impaired in perfused rat livers with hepatic steatosis. Patients with NAFLD had hyperglucagonemia and increased levels of glucagonotropic amino acids, including alanine in particular. Both glucagon and alanine levels were reduced after diet-induced reduction in Homeostatic Model Assessment for Insulin Resistance (HOMA-IR, a marker of hepatic steatosis).ConclusionsGlucagon regulates amino acid metabolism both non-transcriptionally and transcriptionally. Hepatic steatosis may impair glucagon-dependent enhancement of amino acid catabolism.
| S-EPMC7560169 | biostudies-literature