Remodelling of the translatome controls diet and its impact on tumorigenesis

Haojun Yang, Vincenzo Andrea Zingaro, James Lincoff, Harrison Tom, Satoshi Oikawa, Juan A. Oses-Prieto, Quinn Edmondson, Ian Seiple, Hardik Shah, Shingo Kajimura, Alma L. Burlingame, Michael Grabe and Davide Ruggero ()
Additional contact information
Haojun Yang: UCSF
Vincenzo Andrea Zingaro: UCSF
James Lincoff: UCSF
Harrison Tom: UCSF
Satoshi Oikawa: Harvard Medical School and Howard Hughes Medical Institute
Juan A. Oses-Prieto: UCSF
Quinn Edmondson: UCSF
Ian Seiple: UCSF
Hardik Shah: The University of Chicago
Shingo Kajimura: Harvard Medical School and Howard Hughes Medical Institute
Alma L. Burlingame: UCSF
Michael Grabe: UCSF
Davide Ruggero: UCSF

Nature, 2024, vol. 633, issue 8028, 189-197

Abstract: Abstract Fasting is associated with a range of health benefits1–6. 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 fasting7,8. 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 source9,10 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.

Date: 2024
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DOI: 10.1038/s41586-024-07781-7

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