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ROS-induced translation impairment underlies ZAK-mediated metabolic decline in obesity and aging

ABSTRACT: The ribotoxic stress response (RSR) denotes a signaling pathway in which the p38 and JNK-activating MAP3 kinase ZAK senses stalling and/or collision of ribosomes with unknown physiological implications. Here, we show that reactive oxygen species (ROS)-generating agents robustly trigger translational impairment and ZAK activation. As a testament to the physiological importance of this signaling pathway, zebrafish larvae deficient for the ZAK kinase are protected from ROS-induced pathology and death. Furthermore, livers of mice fed a ROS-generating and obesogenic diet accrue ZAK-activating and antioxidant-reversed ribosomal stalls and collisions. Highlighting a role for the RSR in metabolic regulation, ZAK knockout (KO) mice are protected from developing insulin resistance and liver steatosis under these conditions. Finally, aged chow-fed ZAK KO mice do not display the normal hallmarks of metabolic aging. In sum, our work highlights ROS-induced translational impairment as a physiological activation signal for ZAK that underlies metabolic adaptation in obesity and aging.

ORGANISM(S): Mus musculus

PROVIDER: GSE235700 | GEO | 2023/10/23

REPOSITORIES: GEO

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ROS-induced translation impairment underlies ZAK-mediated metabolic decline in obesity and aging

Project description:The ribotoxic stress response (RSR) denotes a signaling pathway in which the p38 and JNK-activating MAP3 kinase ZAKalpha senses stalling and/or collision of ribosomes with unknown physiological implications. Here, we show that reactive oxygen species (ROS)-generating agents robustly trigger translational impairment and ZAKalpha activation. As a testament to the physiological importance of this signaling pathway, zebrafish larvae deficient for the ZAKalpha kinase are protected from ROS-induced pathology and death. Furthermore, livers of mice fed a ROS-generating and obesogenic diet accrue ZAKalpha-activating and antioxidant-reversed ribosomal stalls and collisions. Highlighting a role for the RSR in metabolic regulation, ZAK knockout (KO) mice are protected from developing insulin resistance and liver steatosis under these conditions. Finally, aged chow-fed ZAK KO mice do not display the normal hallmarks of metabolic aging. In sum, our work highlights ROS-induced translational impairment as a physiological activation signal for ZAKalpha that underlies metabolic adaptation in obesity and aging.

2023-11-16 | GSE213774 | GEO

ROS-induced ribosome stalling and collision underlies ZAKalpha-mediated metabolic decline in obesity and aging

Project description:The ribotoxic stress response (RSR) denotes a signaling pathway in which the p38 and JNK-activating MAP3 kinase ZAKalpha senses stalling and/or collision of ribosomes with unknown physiological implications. Here, we show that reactive oxygen species (ROS)-generating agents robustly trigger translational impairment and ZAKalpha activation. Underscoring the physiological importance of this signaling pathway, zebrafish larvae deficient for the ZAKalpha kinase are protected from ROS-induced pathology and death. Furthermore, livers of mice fed a ROS-generating and obesogenic diet exhibit ZAKalpha-activating changes in ribosomal elongation dynamics. Highlighting a role for the RSR in metabolic regulation, ZAK knockout (KO) mice are protected from developing high-fat diet-induced blood glucose intolerance and liver steatosis under these conditions. Finally, ZAK ablation slows animals from developing hallmarks of metabolic aging. In sum, our work highlights ROS-induced translational impairment as a physiological activation signal for ZAKalpha that underlies metabolic adaptation in obesity and aging.

2024-02-01 | PXD043071 | Pride

Stalled ribosomes are signals for metabolic regulation by the ribotoxic stress response

Project description:Impairment of translation can lead to stalling and collision of ribosomes which constitute an activation platform for several ribosomal stress-surveillance pathways. Among these is the Ribotoxic Stress Response (RSR), where ribosomal sensing by the MAP3K ZAKa leads to activation of p38 and JNK kinases. Despite these insights, the physiological ramifications of ribosomal impairment and downstream RSR signaling remain elusive. Here we show that stalling of ribosomes is sufficient to activate ZAKa. In response to amino acid deprivation and full nutrient starvation, RSR impacts on the ensuing metabolic responses in cells, nematodes and mice. The RSR-regulated responses in these model systems include regulation of AMPK and mTOR signaling, survival under starvation conditions, stress hormone production and regulation of blood sugar control. In addition, ZAK-/- mice present with a lean phenotype. Our work highlights stalled ribosomes as metabolic signals and demonstrates a role for RSR signaling in metabolic regulation.

2022-11-16 | GSE205191 | GEO

ZAKα Recognizes Stalled Ribosomes through Partially Redundant Sensor Domains

Project description:Impairment of ribosome function activates the MAPKKK ZAK, leading to activation of mitogen-activated protein (MAP) kinases p38 and JNK and inflammatory signaling. The mechanistic basis for activation of this ribotoxic stress response (RSR) re-mains completely obscure. We show that the long isoform of ZAK (ZAKα) directly associates with ribosomes by inserting its flexible C terminus into the ribosomal intersubunit space. Here, ZAKα binds helix14 of 18S ribosomal RNA (rRNA). An adjacent domainin ZAKa also probes the ribosome, and together, these sensor domains are critically required for RSR activation after inhibition of both the E-site, the peptidyl transferase center (PTC), and ribotoxinaction. Finally, we show that ablation of the RSR response leads to organismal phenotypes and decreased lifespan in the nematode Caenorhabditis elegans (C. elegans). Our findings yield mechanistic insight into how cells detect ribotoxic stress and provide experimental in vivo evidence for its physiological importance.

2020-04-15 | GSE131201 | GEO

Female Mice Lacking p47phox Have Altered Adipose Tissue Gene Expression and are Protected against High Fat-Induced Obesity and Metabolic Syndrome

Project description:Oxidative stress in adipose tissue and liver has been linked to the development of obesity. NADPH oxidases (NOX) enzymes are a major source of reactive oxygen species (ROS). The current study was designed to determine if NOX2-generated ROS play a role in development of obesity and metabolic syndrome after high fat feeding. Wild type (WT) mice and mice lacking the cytosolic NOX2 activated protein p47phox (P47KO) were fed AIN-93G diets or high fat diets (HFD) containing 45% fat and 0.5% cholesterol for 13 weeks from weaning. Affymetrix array analysis revealed dramatically less expression of mRNA of genes linked to energy metabolism, adipocyte differentiation (PPARM-NM-3, Runx2) and fatty acid uptake (CD36, lipoprotein lipase) in fat pads from female HFD-P47KO mice compared to HFD-WT females. These data suggest that NOX2 is an important regulator of metabolic homeostasis and that NOX2-associated ROS plays an important role in development of diet-induced obesity particularly in the female fat pads from p47phox and wild type fed a high fat or control diet

2012-11-01 | E-GEOD-41932 | biostudies-arrayexpress

A Molecular Portrait of the replication stress response defects via Genome-wide Transcriptome Profiling

Project description:Defects in replication stress response (RSR) allow the survival and proliferation of genomically unstable cells, ultimately leading to tumorigenesis. Therefore, the RSR status can potentially serve as a powerful indicator to predict the possibility of early tumorigenesis. Here, we identified an RSR defects (RSRD) gene signature that robustly predicted RSR status. For the clinical benefit, our identification of RSRD gene signature gives the possibility to assess the risk of early tumorigenesis in the precancerous patients. Various shRNAs that target genes involved in replication stress response were transfected in MCF-10A non-transformed breast cell lines after oncogenic cyclin E overexpressed. All MCF-10A variants were seeded 200000 at 10 cm plate. Cells were harvested after 48 hours culturing and used for gene expression profiling.

2016-02-29 | E-GEOD-59227 | biostudies-arrayexpress

A Molecular Portrait of the replication stress response defects via Genome-wide Transcriptome Profiling

2016-02-29 | GSE59227 | GEO

ZAK activation on colliding ribosomes triggers SAPK signaling pathways to regulate cell fate

Project description:Problems arising during translation of mRNAs lead to ribosome stalling and collisions with trailing ribosomes. These collisions are known to trigger a series of events including degradation of the stalled nascent polypeptide, decay of the problematic mRNAs, and ribosome rescue. However, the systemic cellular response of ribosome collision has not been explored. Here, we uncover a novel function for ribosome collisions in signal transduction. Using multiple translation elongation inhibitors and cellular stress conditions, we show that ribosome collisions activate both the SAPK (Stress Activated Protein Kinase) and GCN2-mediated cellular stress response pathways that lead to apoptosis and the integrated stress response (ISR), respectively. We further show that the MAPKKK ZAK functions as the sentinel for ribosome collisions, and ZAK is required for activation of both SAPKs p38/JNK and GCN2 signaling pathways. Selective ribosome profiling and biochemistry demonstrate that ZAK preferentially associates with the minimal unit of colliding ribosomes, the disome, inducing ZAK phosphorylation. While ZAK associates with elongating ribosomes under non-stressed conditions, activation of ZAK is specifically trigger by colliding ribosomes. Together, these results provide new insights into how perturbation of translational homeostasis, as read-out by colliding ribosomes, regulates cell fate.

2020-08-18 | GSE141459 | GEO

Genome-wide analysis of gene expression in DJ-1 deficient muscle cells

Project description:Excessive reactive oxygen species (ROS) underlie the pathogenesis of multiple disorders. Nevertheless, physiological levels of ROS are required for intracellular signalling and maintenance of metabolic homeostasis. DJ-1, a Parkinson’s disease-associated protein, is involved in the regulation of oxidative stress. Our aim in this study was to determine the effect of DJ-1 disruption on gene expression in muscle cells. To this end, we transfected a murine myoblast cell line, C2C12 cells with siRNA targeting DJ-1.

2014-11-07 | GSE63051 | GEO

Dietary amino acid source elicits sex-specific metabolic response to diet-induced NAFLD in murine model.

Project description:Non-alcoholic fatty liver disease (NAFLD) is a sexually dimorphic disease influenced by dietary factors. Here, we assess the metabolic and hepatic effects of dietary amino acid (AA) source in Western diet (WD)-induced NAFLD in male and female mice. The AA source was either casein or a free AA mixture mimicking the composition of casein. As expected, males fed a casein-based WD displayed glucose intolerance, fasting hyperglycemia, and insulin-resistance and developed NAFLD associated with changes in hepatic gene expression and dysbiosis. In contrast, males fed the AA-based WD showed no steatosis, a similar gene expression profile as males fed a control diet, and a distinct microbiota composition compared to males fed a casein-based WD. Females were protected against WD-induced liver damage, hepatic gene expression, and gut microbiota changes regardless of the AA source. Thus, free dietary AA intake prevents the unhealthy metabolic outcomes of a WD in a sex-specific manner.

2024-01-01 | GSE234591 | GEO

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