Descrizione del progetto
Come le cellule percepiscono e rispondono allo stress
Sotto stress, le cellule reagiscono: si impegnano in varie strategie per evitare danni al proteoma cellulare. La domanda è: come fanno? Il progetto RiboStress, finanziato dal CER, si concentrerà sulla comprensione del modo in cui i processi cellulari di sintesi delle proteine vengono rimodellati in risposta allo stress. In particolare, il progetto utilizzerà un approccio all’avanguardia per l’imaging 3D ad alta risoluzione, denominato crio-tomografia elettronica (cryo-ET), che consente di visualizzare i ribosomi (l’apparato cellulare della sintesi proteica) nel loro ambiente cellulare nativo a livello di dettaglio molecolare. Il progetto si baserà sul lavoro precedente e integrerà nuove soluzioni di elaborazione delle immagini. Inoltre, getterà nuova luce sul modo in cui le cellule cercano di contrastare lo squilibrio dell’omeostasi proteica (un segno distintivo delle malattie neurodegenerative). I risultati mostreranno come le strategie per evitare i danni incidano sulla struttura e sull’organizzazione molecolare delle cellule.
Obiettivo
Many cellular and extracellular events cause perturbations of protein homeostasis by affecting either de novo protein folding or by destabilizing already folded proteins. Under such proteotoxic stress conditions, cells engage in various strategies to avoid further damage to the cellular proteome, e.g. by timely modulation of translation activity and specificity, or by resolving the underlying events.
Our overall goal is to dissect from a unique structural angle how such damage avoidance strategies impact on the structure and molecular organization of the translation machinery by directly imaging their effects on ribosome structure, supramolecular organization and distribution in a cellular context with cryo-electron tomography (cryo-ET), an innovative imaging approach unique in its capability to pro-vide highly detailed three-dimensional structural information on macromolecular complexes in their cellular environment. Building on my pioneering work in the field of cryo-ET and integrating novel image processing solutions that have recently marked a breakthrough in the field, we will dissect at unprecedented resolution how the cellular translation machinery is remodeled i) after a general heat-shock, ii) during the Endoplasmic Reticulum unfolded protein response and iii) during persistent translational stalling triggering ribosome-associated quality control.
Work included in this proposal will provide detailed structural and mechanistic insights into how cells try to counteract an imbalance of protein homeostasis - a hallmark of neurodegenerative diseases. It thus seems almost certain that key concepts emerging from our studies will have direct implications on mechanistic understanding of central pathological principles underlying these diseases.
Campo scientifico
Programma(i)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Argomento(i)
Meccanismo di finanziamento
ERC - Support for frontier research (ERC)Istituzione ospitante
69117 Heidelberg
Germania