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

Michela Di Michele; Aurore Attina; Pierre‐François Roux; Imène Tabet; Laguesse Sophie; Florido Javier; Houdeville Morane; Armelle Choquet; Encislai Betty; Giuseppe Arena; Carlo De Blasio; Olivia Wendling; François-Xavier Frénois; Laura Papon; Lucille Stuani; Maryse Fuentes; Jahanault-Tagliani Céline; Rousseau Mélanie; Justine Guégan; Yoan Buscail; Pierrick Dupré; Henri‐Alexandre Michaud; Geneviève Rodier; Floriant Bellvert; Hanna Kulyk; Carole Ferraro‐Peyret; Mathieu Hugo; Close Pierre; Rapino Francesca; Cédric Chaveroux

doi:10.1101/2022.12.19.521032

Developmental BiologybioRxivDec 19, 2022

Preprint

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

Michela Di Michele iD, Aurore Attina iD, Pierre‐François Roux iD, Imène Tabet iD, Laguesse Sophie, Florido Javier, Houdeville Morane, Armelle Choquet iD, Encislai Betty, Giuseppe Arena iD, Carlo De Blasio iD, Olivia Wendling, François-Xavier Frénois iD, Laura Papon, Lucille Stuani iD, Maryse Fuentes, Jahanault-Tagliani Céline, Rousseau Mélanie, Justine Guégan iD, Yoan Buscail, Pierrick Dupré iD, Henri‐Alexandre Michaud iD, Geneviève Rodier iD, Floriant Bellvert iD, Hanna Kulyk iD, , Le Cam Laurent

Abstract

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.

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