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PRINCIPAL PUBLICATION AND AUTHORS

Nucleoside Diphosphate Kinases 1 and 2 regulate a liver protective response to a high-fat diet, D. Iuso (a), I. Garcia-Saez (b), Y. Couté (c), Y. Yamaryo-Botté (a), E. Boeri Erba (b), A. Adrait (c), N. Zeaiter (d), M. Tokarska-Schlattner (d), Z. Macek Jilkova (a,e), F. Boussouar (a), S. Barral (a), L. Signor (b), K. Couturier (d), A. Hajmirza (a), F. Chuffart (a), E. Bourova-Flin (a), A.-L. Vitte (a), L. Bargier (f), D. Puthier (f), T. Decaens (a,e), S. Rousseaux (a), C. Botté (a), U. Schlattner (g), C. Petosa (b), S. Khochbin (a), Sci. Adv. 9, eadh0140 (2023); https:/doi.org/10.1126/sciadv.adh0140 (a) Univ. Grenoble Alpes, CNRS, INSERM, Institute for Advanced Biosciences, La Tronche (France) (b) Univ. Grenoble Alpes, CNRS, CEA, Institut de Biologie Structurale, Grenoble (France) (c) Univ. Grenoble Alpes, INSERM, CEA, BioSanté, Grenoble (France) (d) Univ. Grenoble Alpes, INSERM, Laboratory of Fundamental and Applied Bioenergetics, Grenoble (France) (e) CHU Grenoble Alpes, Service d hépato-gastroentérologie, La Tronche (France) (f) Aix Marseille Université, INSERM, TAGC, TGML, Marseille (France) (g) Univ. Grenoble Alpes, INSERM, Institut Universitaire de France, Laboratory of Fundamental and Applied Bioenergetics, Grenoble (France)

REFERENCES

[1] M. Wallace, C.M. Metallo, Semin. Cell Dev. Biol. 108, 65-71 (2020). [2] F. Ameer et al., Metabolism 63, 895-902 (2014).

also binds to acetyl-CoA prompted a more detailed investigation via a combination of structural, biophysical, genetic and epigenetic approaches.

Crystallographic data collected at beamline ID30A-1 revealed that NME1 recognises acetyl-CoA through the same binding site that recognises ATP and other nucleotides. Despite the similarity with ATP, NME1 recognises the nucleotide moiety of acetyl-CoA by a distinct binding mode that is critically dependent on the ligand s 3 phosphate group (Figure 19). Meanwhile, native mass spectrometry combined with biochemical assays showed that acetyl-CoA binding by NME1 is inhibited by ATP-mediated phosphorylation and is hence sensitive to the cellular energy status. Strikingly, when fed a high- fat diet, a mouse knockout model with greatly reduced NME1/2 levels exhibited excessive triglyceride synthesis and liver steatosis (fat buildup). In liver cells, NME1/2 was found to mediate a gene transcriptional response to a high-fat diet via the targeted acetylation of histones that inhibits fatty acid accumulation by repressing genes encoding key transcription factors involved in DNL and fatty acid metabolism.

These findings identify NME1/2 as a key regulator of the competing processes of histone acetylation and fatty acid synthesis. The results shed important light on how DNL is regulated and reveal a previously unsuspected level of cross-talk between metabolic and epigenetic pathways.