ROS-induced ribosome impairment underlies ZAK α-mediated metabolic decline in obesity and aging

Science. 2023 Dec 8;382(6675):eadf3208. doi: 10.1126/science.adf3208. Epub 2023 Dec 8.ABSTRACTThe ribotoxic stress response (RSR) is a signaling pathway in which the p38- and c-Jun N-terminal kinase (JNK)-activating mitogen-activated protein kinase kinase kinase (MAP3K) ZAKα senses stalling and/or collision of ribosomes. Here, we show that reactive oxygen species (ROS)-generating agents trigger ribosomal impairment and ZAKα activation. Conversely, zebrafish larvae deficient for ZAKα are protected from ROS-induced pathology. Livers of mice fed a ROS-generating diet exhibit ZAKα-activating changes in ribosomal elongation dynamics. Highlighting a role for the RSR in metabolic regulation, ZAK-knockout mice are protected from developing high-fat high-sugar (HFHS) diet-induced blood glucose intolerance and liver steatosis. Finally, ZAK ablation slows animals from developing the hallmarks of metabolic aging. Our work highlights ROS-induced ribosomal impairment as a physiological activation signal for ZAKα that underlies metabolic adaptation in obesity and aging.PMID:38060659 | DOI:10.1126/science.adf3208
Source: Genomics Proteomics ... - Category: Genetics & Stem Cells Authors: Source Type: research