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

• 成果类型: Article
• 署名作者: Snieckute, Goda; Ryder, Laura; Vind, Anna Constance; Wu, Zhenzhen; Arendrup, Frederic Schroder; Stoneley, Mark; Chamois, Sebastien; Martinez-Val, Ana; Leleu, Marion; Dreos, Rene; Russell, Alexander; Gay, David Michael; Genzor, Aitana Victoria; Choi, Beatrice So-Yun; Basse, Astrid Linde; Sass, Frederike; Dall, Morten; Dollet, Lucile Chantal Marie; Blasius, Melanie; Willis, Anne E.; Lund, Anders H.; Treebak, Jonas T.; Olsen, Jesper Velgaard; Poulsen, Steen Seier; Pownall, Mary Elizabeth; Jensen, Benjamin Anderschou Holbech; Clemmensen, Christoffer; Gerhart-Hines, Zach; Gatfield, David; Bekker-Jensen, Simon
• 署名单位: University of Copenhagen; University of Copenhagen; University of Copenhagen; University of Cambridge; University of Lausanne; University of Copenhagen; University of Lausanne; University of Lausanne; Swiss Federal Institutes of Technology Domain; Ecole Polytechnique Federale de Lausanne; University of York - UK; University of Copenhagen; Novo Nordisk Foundation; University of Copenhagen
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-9007
• DOI: 10.1126/science.adf3208
• 发表日期: 2023-12-08
• 页码: 1135-+
• 关键词: increased oxidative stress; quality-control; activation; jnk; responses; pathways; kinases; IMPACT; injury; white

摘要

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) 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.