Snieckute, GodaRyder, LauraVind, Anna ConstanceWu, ZhenzhenArendrup, Frederic SchroderStoneley, MarkChamois, SebastienMartinez-Val, AnaLeleu, MarionDreos, ReneRussell, AlexanderGay, David MichaelGenzor, Aitana VictoriaChoi, Beatrice So-YunBasse, Astrid LindeSass, FrederikeDall, MortenDollet, Lucile Chantal MarieBlasius, MelanieWillis, Anne E.Lund, Anders H.Treebak, Jonas T.Olsen, Jesper VelgaardPoulsen, Steen SeierPownall, Mary ElizabethJensen, Benjamin Anderschou HolbechClemmensen, ChristofferGerhart-Hines, ZachGatfield, DavidBekker-Jensen, Simon2024-02-232024-02-232024-02-232023-12-0810.1126/science.adf3208https://infoscience.epfl.ch/handle/20.500.14299/205476WOS:001156091000003The 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) ZAK alpha senses stalling and/or collision of ribosomes. Here, we show that reactive oxygen species (ROS)-generating agents trigger ribosomal impairment and ZAK alpha activation. Conversely, zebrafish larvae deficient for ZAK alpha are protected from ROS-induced pathology. Livers of mice fed a ROS-generating diet exhibit ZAK alpha-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 ZAK alpha that underlies metabolic adaptation in obesity and aging.Increased Oxidative StressQuality-ControlActivationJnkResponsesPathwaysKinasesImpactInjuryWhitetext::journal::journal article::research article