Description du projet
Comment les cellules quittent-elles leurs activités pour lutter contre le stress
Les modifications des conditions extracellulaires peuvent endommager la structure et la fonction des macromolécules. Par exemple, un déséquilibre prolongé entre la génération de radicaux libres et la disponibilité d’antioxydants (stress oxydatif) peut endommager les cellules, les protéines et l’ADN de l’organisme. La réponse cellulaire au stress est contrôlée par une voie adaptative hautement conservée, la réponse intégrée au stress. Un peu comme un triage cellulaire, la cellule consacre la plus grande partie de son énergie translationnelle aux ARNm liés au stress, tout en interrompant la traduction d’autres ARNm. Toutefois, les mécanismes ne sont pas bien compris. Le projet mRNAstress mène des études monomoléculaires sur la traduction de l’ARN, tout en manipulant des facteurs de stress. Lever le voile sur les mécanismes à l’origine de la reprogrammation translationnelle en réponse au stress a des implications profondes pour la santé et les maladies humaines.
Objectif
Cells are frequently exposed to stress conditions, which can disrupt cellular homeostasis and result in cell death. To minimize the damage and adapt to the stress condition, eukaryotic cells employ a highly conserved signaling pathway, the integrated stress response, which integrates a variety of intrinsic and extrinsic stress signals to reprogram mRNA translation. Consequently, translation of most mRNAs is inhibited to conserve energy, while a select group of stress-related mRNAs is preferentially translated to promote recovery and restore homeostasis. This preferential translation of stress-related mRNAs depends on special sequence elements called upstream open reading frames (uORF), but the molecular mechanisms behind this process remain largely unclear. To investigate the translational reprogramming during cellular stress, I will exploit recent advances in single-molecule imaging of mRNA translation in living human cells.
First, to understand how uORFs facilitate the preferential translation of stress-related transcripts in stressed cells, I will apply single-molecule imaging of mRNA translation to measure the translational dynamics at different start codons of uORF-containing reporter mRNAs. Next, I will test how the translational reprogramming is affected by the formation of stress-inducible ribonucleoprotein granules (stress granules). To this end, I will combine the single-molecule imaging of mRNA translation with imaging and optogenetic manipulation of stress granules. Last, to complement the single-molecule imaging approach, the same reporter mRNAs will be subjected to proximity-dependent labelling assays in order to identify novel factors that facilitate stress-induced translation.
Together, this project will provide important insights into the regulation of mRNA translation during cellular stress. This will also expand our understanding of pathological conditions that involve misregulation of the integrated stress response.
Champ scientifique
Programme(s)
Régime de financement
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinateur
4058 Basel
Suisse