Remodelling of the translatome controls diet and its impact on tumorigenesis

• 成果类型: Article
• 署名作者: Yang, Haojun; Zingaro, Vincenzo Andrea; Lincoff, James; Tom, Harrison; Oikawa, Satoshi; Oses-Prieto, Juan A.; Edmondson, Quinn; Seiple, Ian; Shah, Hardik; Kajimura, Shingo; Burlingame, Alma L.; Grabe, Michael; Ruggero, Davide
• 署名单位: University of California System; University of California San Francisco; UCSF Medical Center; UCSF Helen Diller Family Comprehensive Cancer Center; University of California System; University of California San Francisco; University of California System; University of California San Francisco; University of California System; University of California San Francisco; University of California System; University of California San Francisco; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Beth Israel Deaconess Medical Center; Howard Hughes Medical Institute; Robert H. Lurie Comprehensive Cancer Center; University of Chicago; University of California System; University of California San Francisco
• 刊物名称: Nature
• ISSN/ISSBN: 0028-5335
• DOI: 10.1038/s41586-024-07781-7
• 发表日期: 2024-09-05
• 页码: 189-+
• 关键词: activated protein-kinase; eif4e phosphorylation; fatty-acid; ampk; initiation; binding; cancer; alpha; mnk1; modulation

摘要

Fasting is associated with a range of health benefits(1-6). How fasting signals elicit changes in the proteome to establish metabolic programmes remains poorly understood. Here we show that hepatocytes selectively remodel the translatome while global translation is paradoxically downregulated during fasting(7,8). We discover that phosphorylation of eukaryotic translation initiation factor 4E (P-eIF4E) is induced during fasting. We show that P-eIF4E is responsible for controlling the translation of genes involved in lipid catabolism and the production of ketone bodies. Inhibiting P-eIF4E impairs ketogenesis in response to fasting and a ketogenic diet. P-eIF4E regulates those messenger RNAs through a specific translation regulatory element within their 5 untranslated regions (5 ' UTRs). Our findings reveal a new signalling property of fatty acids, which are elevated during fasting. We found that fatty acids bind and induce AMP-activated protein kinase (AMPK) kinase activity that in turn enhances the phosphorylation of MAP kinase-interacting protein kinase (MNK), the kinase that phosphorylates eIF4E. The AMPK-MNK-eIF4E axis controls ketogenesis, revealing a new lipid-mediated kinase signalling pathway that links ketogenesis to translation control. Certain types of cancer use ketone bodies as an energy source(9,10) that may rely on P-eIF4E. Our findings reveal that on a ketogenic diet, treatment with eFT508 (also known as tomivosertib; a P-eIF4E inhibitor) restrains pancreatic tumour growth. Thus, our findings unveil a new fatty acid-induced signalling pathway that activates selective translation, which underlies ketogenesis and provides a tailored diet intervention therapy for cancer.