| First Author | Snieckute G | Year | 2023 |
| Journal | Science | Volume | 382 |
| Issue | 6675 | Pages | eadf3208 |
| PubMed ID | 38060659 | Mgi Jnum | J:344263 |
| Mgi Id | MGI:7571637 | Doi | 10.1126/science.adf3208 |
| Citation | Snieckute G, et al. (2023) ROS-induced ribosome impairment underlies ZAKalpha-mediated metabolic decline in obesity and aging. Science 382(6675):eadf3208 |
| abstractText | 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) ZAKalpha senses stalling and/or collision of ribosomes. Here, we show that reactive oxygen species (ROS)-generating agents trigger ribosomal impairment and ZAKalpha activation. Conversely, zebrafish larvae deficient for ZAKalpha are protected from ROS-induced pathology. Livers of mice fed a ROS-generating diet exhibit ZAKalpha-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 ZAKalpha that underlies metabolic adaptation in obesity and aging. |
