Mechanisms of Translation Control in Humans

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ABSTRACT Protein synthesis, or translation, connects genotype to phenotype in all forms of life. The Cate lab has a longstanding interest in the mechanisms of protein synthesis, from universal principles gleaned from bacterial translation to the basis of translation regulation in humans. This application tackles fundamental questions about how translation is regulated in humans. We propose to explore the regulation of translation initiation in specific cells and tissues, and mechanisms of translation elongation that affect the speed and accuracy of the ribosome. We think these two broad lines of investigation will lead to many discoveries about protein synthesis that could eventually be leveraged to treat human disease. The canonical mechanism of translation initiation in eukaryotes involves many general translation initiation factors. We recently discovered that one of these–eukaryotic initiation factor 3 (eIF3)–serves specialized roles to either activate or repress the translation of specific mRNAs. We also found that eIF3 unexpectedly includes its own 5’-m7G cap binding subunit. In this application, we will probe how and when eIF3 carries out its specific regulatory functions. We will use molecular and structural approaches to decipher how eIF3 and trans-acting factors interact with structured RNA elements to regulate the translation of specific mRNAs. We will also examine the role of eIF3 in regulating translation in activated T cells. Finally, we will determine how eIF3 regulation of T cell receptor translation affects T cell development. Answers to these questions will reveal fundamental insights into translational control and will provide a foundation for future engineering of improved cell-based immunotherapies. Protein targets for many human diseases remain “undruggable” due to their underlying biochemical functions and behavior. These limits to small molecule drug discovery hold back the promise of developing affordable therapeutics. We recently showed that small molecules that bind the ribosome can selectively stall the translation of human proteins, revealing an entirely new mechanism of action that could enable targeting previously “undruggable” proteins. These drug-like compounds directly and selectively modulate the translation of specific nascent polypeptides during translation elongation or termination. We also found these compounds impact ribosome quality control pathways. We will explore whether similar mechanisms are employed by cellular metabolites to regulate the translation of specific mRNAs. We will also map new ribosome quality control pathways that target translation frameshifting, a process sensitive to the mechanisms employed by the drug-like compounds to selectively stall translation. Taken together, these experiments will provide new molecular insights that could aid in the design of new small molecule modulators of human translation.