Project description
Coordinating protein synthesis and folding in metazoans
To function, proteins fold into complex 3D shapes. Since proteins often begin to fold during messenger ribonucleic acid (mRNA) translation, codon choice and transfer ribonucleic acid (tRNA) supply can further this process by modulating translation speed. Scientists don’t know how metazoans exploit this mechanism to ensure protein homeostasis. The EU-funded TransTempoFold project will establish how tRNA pools and the regulatory networks for protein biogenesis and homeostasis are tailored to specialised proteomes in different cell types. It will focus on stem cells and differentiated progeny lines and develop a method to modulate cellular tRNA pools in vivo. The project will define how diverse metazoan cell proteomes are established and maintained and reveal why some cells tolerate misfolded proteins better than others.
Objective
Proteins function only after folding into complex three-dimensional shapes. Loss of protein conformation is detrimental for cellular health, and a hallmark of aging and diverse human diseases. To ensure proteome integrity, cells rely on an intricate interplay between protein synthesis, folding, and quality control. Since proteins often begin to fold during mRNA translation, codon choice and tRNA supply can promote this process by modulating translation speed. How metazoans exploit this mechanism to ensure protein homeostasis over a wide range of cells and tissues, or why some cell types are more vulnerable to translation defects and proteome damage remains unknown. Here, I will define how tRNA pools and the regulatory networks for protein biogenesis and homeostasis are tailored to specialized proteomes in different cell types. I propose a multiscale systems approach centred around: i) stem cells and differentiated progeny lines as a powerful model system, and ii) a novel method to modulate cellular tRNA pools in vivo. Isogenic lines of a range of normal cellular states will be created through the differentiation of human pluripotent stem cells into neuronal and cardiac lineages. In these lineages, I will first quantitate tRNA expression and abundance, and dissect their impact on translation dynamics with ribosome profiling. Second, I will use systematic depletion of individual tRNAs to explore how different cell types respond to imbalanced tRNA pools, and define how mRNA sequence and protein structure patterns program protein folding. Third, I will use loss-of-function screens to uncover evolutionarily conserved regulators of proteome integrity as a function of cell identity. This project will define how diverse metazoan cell proteomes are established and maintained, and reveal why some cells tolerate misfolded proteins better than others.
Fields of science
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Funding Scheme
ERC-STG - Starting GrantHost institution
80539 Munchen
Germany