E4F1 coordinates pyruvate metabolism and the activity of the elongator complex to ensure translation fidelity during brain development
Abstract
AbstractPyruvate 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 plays an essential role during brain development. Using genetically engineered mouse model and primary neuronal cells, we identify 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, ensures proper translation fidelity and cell survival in the central nervous system (CNS) during mouse embryonic development. Furthermore, analysis of PDH-deficient cells highlight a crosstalk linking the PDC to ELP3 expression that is perturbed in LS patients.
Article Details
Authors (45)
Michela Di Michele
Aurore Attina
Pierre-François Roux
Imène Tabet
Sophie Laguesse
Javier Florido
Morane Houdeville
Armelle Choquet
Betty Encislai
Giuseppe Arena
Department of Psychology, University of Amsterdam
Carlo De Blasio
Olivia Wendling
François-Xavier Frenois
Laura Papon
Lucille Stuani
Maryse Fuentes
Céline Jahannault Talignani
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