Project description
How cells sense and respond to stress
Under stress, cells respond. They engage in various strategies to avoid damage to the cellular proteome. The question is how. The ERC-funded RiboStress project will focus on understanding how cellular processes for synthesising proteins are remodelled in response to stress. Specifically, the project will use a cutting-edge approach to high-resolution 3D imaging, termed cryo-electron tomography (cryo-ET), which enables visualisation of ribosomes (the cellular machinery of protein synthesis) in their native cellular environment at molecular detail. The project will build on previous work and integrate novel image processing solutions. It will also shed new light on how cells try to counteract an imbalance of protein homeostasis (a hallmark of neurodegenerative diseases). The findings will show how damage avoidance strategies impact cells’ structure and molecular organisation.
Objective
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.
Fields of science
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Topic(s)
Funding Scheme
ERC - Support for frontier research (ERC)Host institution
69117 Heidelberg
Germany