E4F1 COORDINATES PYRUVATE METABOLISM AND THE ACTIVITY OF THE ELONGATOR COMPLEX TO ENSURE TRANSLATION FIDELITY DURING BRAIN DEVELOPMENT

Pyruvate metabolism defects lead to severe neuropathies such as the Leigh syndrome (LS) but the molecular mechanisms underlying neuronal cell death remain poorly understood. Here, we unravel a connection between pyruvate metabolism and the regulation of the epitranscriptome that is relevant to LS pa...

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Veröffentlicht in:Nature communications
Hauptverfasser: Michela, Di Michele, Aurore, Attina, Pierre-François, Roux, Imène, Tabet, Sophie, Laguesse, Javier, Florido, Morane, Houdeville, Armelle, Choquet, Betty, Encislai, Giuseppe, Arena, Carlo, De Blasio, Olivia, Wendling, Francois-Xavier, Frenois, Laura, Papon, Lucille, Stuani, Maryse, Fuentes, Céline, Jahanault-Tagliani, Mélanie, Rousseau, Justine, Guégan, Yoan, Buscail, Pierrick, Dupré, Henri-Alexandre, Michaud, Geneviève, Rodier, Floriant, Bellvert, Hanna, Kulyk, Carole, Ferraro Peyret, Hugo, Mathieu, Pierre, Close, Francesca, Rapino, Cédric, Chaveroux, Nelly, Pirot, Lucie, Rubio, Adeline, Torro, Tania, Sorg, Fabrice, Ango, Christophe, Hirtz, Vincent, Compan, Elise, Lebigot, Andrea, Legati, Daniele, Ghezzi, Laurent, Nguyen, Alexandre, David, Claude, Sardet, Matthieu, Lacroix, Laurent, Le Cam
Format: Paper Journal Article
Sprache:Englisch
Veröffentlicht: Cold Spring Harbor Laboratory 02.10.2024
Nature Publishing Group
Ausgabe:1.2
Schlagworte:
Biochemistry, Molecular Biology
Developmental Biology
Life Sciences
pyruvate metabolism
translation
Leigh syndrome
E4F1
Elongator complex
integrated stress response
ISSN:2041-1723, 2692-8205, 2041-1723
Online-Zugang:Volltext
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Zusammenfassung:Pyruvate metabolism defects lead to severe neuropathies such as the Leigh syndrome (LS) but the molecular mechanisms underlying neuronal cell death remain poorly understood. Here, we unravel a connection between pyruvate metabolism and the regulation of the epitranscriptome that is relevant to LS pathogenesis. We identified the transcription factor E4F1 as a key coordinator of AcetylCoenzyme A (AcCoA) production by the pyruvate dehydrogenase complex (PDC) and its utilization as an essential co-factor by the Elongator complex to acetylate tRNAs at the wobble position uridine 34 (U34). E4F1-mediated direct transcriptional regulation of Dlat and Elp3, two genes encoding key subunits of the PDC and of the Elongator complex, respectively, ensured proper translation fidelity and cell survival in the central nervous system (CNS) during mouse embryonic development. Furthermore, analysis of PDH-deficient cells highlighted a crosstalk linking the PDC to ELP3 expression that is perturbed in LS patients.
Bibliographie:Competing Interest Statement: The authors have declared no competing interest.
ISSN:2041-1723
2692-8205
2041-1723
DOI:10.1101/2022.12.19.521032