ROS-induced translation impairment underlies ZAK-mediated metabolic decline in obesity and aging
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA882418 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21640337.fastq.gz | Fastqsanger.gz | |||
| SRR21640338.fastq.gz | Fastqsanger.gz | |||
| SRR21640339.fastq.gz | Fastqsanger.gz | |||
| SRR21640340.fastq.gz | Fastqsanger.gz | |||
| SRR21640341.fastq.gz | Fastqsanger.gz |
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Project description: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.
2023-10-23 | GSE235700 | GEO
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.
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Project description:ROS-induced translation impairment underlies ZAK-mediated metabolic decline in obesity and aging
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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.
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