TY - JOUR
T1 - ROS-induced ribosome impairment underlies ZAKα-mediated metabolic decline in obesity and aging
AU - Snieckute, Goda
AU - Ryder, Laura
AU - Vind, Anna Constance
AU - Wu, Zhenzhen
AU - Arendrup, Frederic Schrøder
AU - Stoneley, Mark
AU - Chamois, Sébastien
AU - Martinez-Val, Ana
AU - Leleu, Marion
AU - Dreos, René
AU - Russell, Alexander
AU - Gay, David Michael
AU - Genzor, Aitana Victoria
AU - Choi, Beatrice So-Yun
AU - Basse, Astrid Linde
AU - Sass, Frederike
AU - Dall, Morten
AU - Dollet, Lucile Chantal Marie
AU - Blasius, Melanie
AU - Willis, Anne E
AU - Lund, Anders H
AU - Treebak, Jonas T
AU - Olsen, Jesper Velgaard
AU - Poulsen, Steen Seier
AU - Pownall, Mary Elizabeth
AU - Jensen, Benjamin Anderschou Holbech
AU - Clemmensen, Christoffer
AU - Gerhart-Hines, Zach
AU - Gatfield, David
AU - Bekker-Jensen, Simon
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
KW - Mice
KW - Animals
KW - Reactive Oxygen Species/metabolism
KW - Zebrafish
KW - Ribosomes/metabolism
KW - Aging
KW - Obesity/genetics
U2 - 10.1126/science.adf3208
DO - 10.1126/science.adf3208
M3 - Journal article
C2 - 38060659
VL - 382
JO - Science
JF - Science
SN - 0036-8075
IS - 6675
M1 - eadf3208
ER -