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

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. Overall design: Comparative ribosome and disome footprints of DISOME-seq (PD) and RIBO-seq (PF) data of mouse livers tissues grown in standard diet and high fat diet