研究人员发现活性氧（ROS）生成剂触发核糖体损伤和ZAKα激活。相反，缺乏ZAKα的斑马鱼幼虫可以免受ROS诱导的病理影响。饲喂促ROS饮食的小鼠肝脏表现出ZAKα激活的核糖体延伸动力学变化。这强调了核糖体毒性应激反应（RSR）在代谢调节中的作用，ZAK基因敲除小鼠可以防止高脂高糖（HFHS）饮食诱导的血糖不耐受和肝脏脂肪变性。最后，ZAK敲除减缓了动物代谢衰老的特征。
这项工作强调ROS诱导的核糖体损伤是ZAKα的生理激活信号，并且是肥胖和衰老中代谢适应的基础。
据介绍，RSR是p38和c-Jun N末端激酶（JNK）激活的丝裂原激活蛋白激酶激酶（MAP3K）ZAKα感知核糖体的阻滞和/或碰撞的信号通路。
附：英文原文
Title: ROS-induced ribosome impairment underlies ZAKα-mediated metabolic decline in obesity and aging
Author: Goda Snieckute, Laura Ryder, Anna Constance Vind, Zhenzhen Wu, Frederic Schrder Arendrup, Mark Stoneley, Sébastien Chamois, Ana Martinez-Val, Marion Leleu, René Dreos, Alexander Russell, David Michael Gay, Aitana Victoria Genzor, Beatrice So-Yun Choi, Astrid Linde Basse, Frederike Sass, Morten Dall, Lucile Chantal Marie Dollet, Melanie Blasius, Anne E. Willis, Anders H. Lund, Jonas T. Treebak, Jesper Velgaard Olsen, Steen Seier Poulsen, Mary Elizabeth Pownall, Benjamin Anderschou Holbech Jensen, Christoffer Clemmensen, Zach Gerhart-Hines, David Gatfield, Simon Bekker-Jensen
Issue&Volume: 2023-12-08
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.
DOI: adf3208
Source: https://www.science.org/doi/10.1126/science.adf3208