mRNAstress · Investigating the molecular mechanisms of translational reprogramming during cellular stress
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2020-08-01 → 2022-07-31
- EU contribution
- €191,149
- Participants
- 1
- Scheme
- MSCA-IF
Lines connect the coordinator with its partners.
Results in brief
Investigating the molecular mechanisms of translational reprogramming during cellular stress
Human cells are frequently exposed to stress conditions such as toxins, oxidative stress, nutrient deprivation or hypoxia. These conditions can inflict damage to cells and potentially lead to cell death. To minimize the damage and adapt to the stress conditions, cells respond by reducing the rate of protein synthesis and boosting various repair pathways. The ability of cells to deal with stress is crucial for longevity of the organism, and it is now clear that defects in cellular stress responses can lead to age-related neurodegenerative disorders and other diseases. Understanding the molecular mechanisms of cellular adaptation to stress is thus crucial for addressing the healthcare challenges faced by ageing populations. More specifically, cells have evolved an adaptive signalling pathway termed the integrated stress response (ISR), which is activated by a broad range of stress signals. The activation of this pathway has three major outcomes in cells: First, global inhibition of mRNA translation leads to reduced protein synthesis and allows cells to conserve energy and nutrients. Second, a small group of stress-related mRNAs are preferentially translated, producing a specific set of proteins that are required for recovery from stress. Third, clustering of mRNA into sub-cellular structures termed stress granules, whose function is largely unclear. The main goal of this project is to unravel the mechanisms that govern the regulation of mRNA translation during the cellular stress response. To do this, we investigate how specific sequence elements allow the preferential translation of stress-related mRNAs, and how stress granules affect mRNA translation.
Data: CORDIS, © European Union
Project objective
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.
Original text from CORDIS.
Participants
- FRIEDRICH MIESCHER INSTITUTE FOR BIOMEDICAL RESEARCH FONDATION · BASELCoordinatorSwitzerland
Links
Data: CORDIS, © European Union