ROS-induced ribosome stalling and collision underlies ZAKalpha-mediated metabolic decline in obesity and aging
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ABSTRACT: 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.
INSTRUMENT(S): Orbitrap Exploris 480
ORGANISM(S): Mus Musculus (mouse)
TISSUE(S): Liver
SUBMITTER: Ana Martinez-Val
LAB HEAD: Jesper V. Olsen
PROVIDER: PXD043071 | Pride | 2024-02-01
REPOSITORIES: Pride
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