# Mechanisms of Translation Control in Humans

> **NIH NIH R35** · UNIVERSITY OF CALIFORNIA BERKELEY · 2023 · $505,651

## Abstract

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.

## Key facts

- **NIH application ID:** 10552291
- **Project number:** 1R35GM148352-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA BERKELEY
- **Principal Investigator:** JAMIE H CATE
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $505,651
- **Award type:** 1
- **Project period:** 2023-03-07 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10552291

## Citation

> US National Institutes of Health, RePORTER application 10552291, Mechanisms of Translation Control in Humans (1R35GM148352-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10552291. Licensed CC0.

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