Science, coauth.: Group Gatfield

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

Goda Snieckute # 1 2Laura Ryder # 1 2Anna Constance Vind # 1 2Zhenzhen Wu 1 2Frederic Schrøder Arendrup 3Mark Stoneley 4Sébastien Chamois 5Ana Martinez-Val 6Marion Leleu 7René Dreos 5Alexander Russell 8David Michael Gay 3Aitana Victoria Genzor 1 2Beatrice So-Yun Choi 9Astrid Linde Basse 10Frederike Sass 10Morten Dall 10Lucile Chantal Marie Dollet 10Melanie Blasius 1 2Anne E Willis 4Anders H Lund 3Jonas T Treebak 10Jesper Velgaard Olsen 6Steen Seier Poulsen 9Mary Elizabeth Pownall 8Benjamin Anderschou Holbech Jensen 9Christoffer Clemmensen 10Zach Gerhart-Hines 10David Gatfield 5Simon Bekker-Jensen 1 2

Science 2023 Dec 8;382(6675):eadf3208. doi: 10.1126/science.adf3208. Epub 2023 Dec 8.


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.