Project description
Exploring ribosomal frameshifting in human cells
Many viruses, including HIV, employ a process known as programmed ribosomal frameshifting (PRF) where, during protein synthesis, the ribosome slips to another position. This process alters the code and leads to the generation of different proteins from the same mRNA, adding another level of gene expression regulation. The EU-funded T-FRAME project aims to study the phenomenon of PRF in human cells and identify the factors that regulate it. Scientists will employ human T lymphocytes and HIV-1 as a model system to investigate the impact of PRF on infection and innate immunity. Results will provide unprecedented knowledge on this alternative pathway to standard decoding and pave the way for the design of novel antiviral therapies.
Objective
The coding region of many genes contains sequence elements that constitute roadblocks during mRNA translation. These roadblocks present problems, but also opportunities for the cell to increase the coding capacity of the genome by so-called programmed ribosome frameshifting (PRF). PRF is a universal gene expression strategy that brings plasticity to the proteome. It is widely studied in viruses and bacteria, yet poorly understood in humans.
My own mechanistic discoveries have highlighted that, regardless of various stimulatory structures and slippery nucleotides involved, PRF in bacterial and viral mRNAs follows one of the two general pathways depending on substrate. In contrast, many questions remain regarding the occurrences of PRF in humans and its regulation by recently discovered trans-acting viral and cellular factors.
In T-FRAME, I will investigate the mechanism of PRF and its role in disease using HIV infection of human-T lymphocytes as an in vivo paradigm. To study molecular details of how trans-factors modulate PRF, I will leverage cutting-edge ensemble and single-molecule techniques to monitor the ribosome as it moves along the mRNA codon per codon. In addition, I will assess mRNA interactions with PRF factors during this process. Using a PRF-RNA-interactome capture assay that we have recently developed, I will search for new trans- factors in human cells. Finally, I will study the translation of T cells and HIV-1 on a global level during infection to understand the full scope and dynamic nature of PRF in this model system.
To summarize, T-FRAME will advance our understanding of how RNA structure and trans-factors shape translation regimes in higher eukaryotes and how deviations from the standard decoding path impact infection and innate immunity. I envision harnessing these findings to develop novel tools for synthetic biology and new design principles for RNA-centric antiviral and immune therapies.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences biochemistry biomolecules proteins proteomics
- natural sciences biological sciences microbiology bacteriology
- medical and health sciences health sciences infectious diseases RNA viruses HIV
- natural sciences biological sciences genetics RNA
- natural sciences biological sciences genetics genomes
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Keywords
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC)
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Call for proposal
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(opens in new window) ERC-2020-STG
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93053 Regensburg
Germany
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