How to Build Up Functional Proteome?
A key factor in ensuring human health and longevity is the homeostasis of proteins, which are the building blocks of our bodies and maintain cell type specific functions. Indeed, loss of proteostasis is a hallmark of aging and neurological diseases. To maintain functional protein synthesis, eukaryotic cells have a quality control system eliminating non-functional ribosomes that can not produce protein [Fujii et al. Genes Dev 2009, EMBO.J 2012]. However, the protein production step, mRNA translation, is highly error-prone to amino acid misincorporation, stop codon readthrough, and ribosomal frameshifting. By focusing on the ribosome, we found a molecular mechanism to increase the accuracy of ribosomal decoding in eukaryotes beyond prokaryotes [Fujii et al. Mol Cell 2018]. We further seek to understand the dynamics of such regulation in mammalian organisms and how regulation contributes to our health.
Key Questions:
- What are the dynamics of translation fidelity between tissues during mammalian development, across aging, and in disease?
- What is the molecular mechanism that regulates the accuracy of ribosomal decoding?
- How can we make ribosomes that do not synthesize trash?
Decoding the Role of mRNA Translation in Cell Signaling
A key factor for the spatiotemporal queue in developing embryos is developmental cell signaling which allows each cell to “know” where they are and what to become. However, all cell signaling has been used multiple times during embryonic development in different contexts and how signaling is specialized for each specific context is still not well understood. Although mRNA translation has been thought as always “on” state, we found that translation of important developmental signaling circuitry including Shh, Wnt, and Hippo signaling are highly repressed and differentially regulated between tissues [Fujii et al. Nat Commun 2017, Dev Cell 2021]. We want to mechanistically understand how translational regulation of signaling transcripts impacts tissue-specific signaling and species-specific tissue patterning.
Key Questions:
- What are the Cis-regulatory elements and trans-acting factors that regulate the translation of signaling transcripts?
- What is the trigger to turn “on” the translation of signaling transcripts?
- What is the impact of translation regulation on cell signaling for tissue specific signaling and species-specific tissue patterning?
Our Approach
We approach these outstanding questions using a variety of model systems such as mice, cultured cells, and yeast and apply state-of-the-art Biochemistry, Genetics, and Genomics to molecularly decode the impact of translation regulation in mammalian development and homeostasis.
