ROS-induced ribosome impairment underlies ZAKα-mediated metabolic decline in obesity and aging
Goda Snieckute # 1 2, Laura Ryder # 1 2, Anna Constance Vind # 1 2, Zhenzhen Wu 1 2, Frederic Schrøder Arendrup 3, Mark Stoneley 4, Sébastien Chamois 5, Ana Martinez-Val 6, Marion Leleu 7, René Dreos 5, Alexander Russell 8, David Michael Gay 3, Aitana Victoria Genzor 1 2, Beatrice So-Yun Choi 9, Astrid Linde Basse 10, Frederike Sass 10, Morten Dall 10, Lucile Chantal Marie Dollet 10, Melanie Blasius 1 2, Anne E Willis 4, Anders H Lund 3, Jonas T Treebak 10, Jesper Velgaard Olsen 6, Steen Seier Poulsen 9, Mary Elizabeth Pownall 8, Benjamin Anderschou Holbech Jensen 9, Christoffer Clemmensen 10, Zach Gerhart-Hines 10, David Gatfield 5, Simon Bekker-Jensen 1 2
Science 2023 Dec 8;382(6675):eadf3208. doi: 10.1126/science.adf3208. Epub 2023 Dec 8.
Abstract
The 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.