New publication in Science by Bekker-Jensen Group

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.

ROS-induced ribosome impairment underlies ZAKα-mediated metabolic decline in obesity and aging.
Snieckute G, Ryder L, Vind AC, Wu Z, Arendrup FS, Stoneley M, Chamois S, Martinez-Val A, Leleu M, Dreos R, Russell A, Gay DM, Genzor AV, Choi BS, Basse AL, Sass F, Dall M, Dollet LCM, Blasius M, Willis AE, Lund AH, Treebak JT, Olsen JV, Poulsen SS, Pownall ME, Jensen BAH, Clemmensen C, Gerhart-Hines Z, Gatfield D, Bekker-Jensen S.
Science. 2023 Dec 8;382(6675):eadf3208