# Mechanism and Regulation of eIF6 in Translation

> **NIH NIH R01** · SAINT LOUIS UNIVERSITY · 2024 · $318,150

## Abstract

PROJECT SUMMARY
Ribosomes are large ribonucleoprotein complexes that are integral to translational control. The assembly and
maturation of ribosomal subunits involves a multitude of trans-acting factors that render the subunits
translationally competent. Maturation of the 60S ribosomal subunit is accomplished by the release of eukaryotic
initiation factor-6 (eIF6) with the help of the maturation factors-SBDS and EFL1-GTPase. eIF6 sterically hinders
association of the 60S and 40S subunits and therefore, its release from 60S is critical to permit interactions
between 60S and the mRNA-bound 40S subunits. In addition, eIF6 is essential for rRNA processing in the
nucleolus and is associated with the translationally stalled 60S-ribosome quality control complex. Given its
essential roles, the spatial and temporal aspects of eIF6 activities and its release from 60S must be tightly
regulated to ensure successful initiation of translation. Impaired release of eIF6 is the defining hallmark of certain
ribosomopathies: Shwachman-Diamond syndrome and RPL10 mutations-driven pediatric leukemias. eIF6 levels
are also deregulated in several cancers and its enhanced expression is associated with a poor prognosis.
Remarkably, restricting eIF6 levels inhibits growth of certain cancers without affecting normal growth. Therefore,
targeting eIF6 and its release from 60S has been proposed to be a desirable therapeutic strategy for cancers
and ribosomopathies. However, we are yet to understand the role of eIF6 in modulating the distinct steps of 60S
assembly and maturation. Also, the molecular mechanisms that regulate eIF6 interactions with the 60S are not
completely understood. Towards understanding these mechanisms, our recent work has identified key residues
in critical interfaces of eIF6 that modulate its interaction with 60S, and our preliminary data provide direct
evidence that the disruption of this interaction is detrimental to cancer cell viability. We have also identified novel
sites of regulation in the C-terminus of eIF6 and have uncovered its importance for controlling translational rates.
Building on these discoveries, in the current proposal we aim to define the mechanistic steps that promote the
release of eIF6 by SBDS, and EFL1 from distinct functional states of 60S and to uncover the role of GTPase
activity of EFL1 using a rigorous set of biochemical, biophysical, and single molecule approaches. In addition,
we aim to uncover the mechanism of allosteric regulation by the C-terminus of eIF6 and elucidate the functional
and phenotypic effects of disease-specific mutations of eIF6 using cellular and in vivo approaches. These studies
will provide crucial mechanistic insight into 60S dynamics and will enable the development of therapeutics
focused on eIF6 and its regulators.

## Key facts

- **NIH application ID:** 10832675
- **Project number:** 5R01GM143179-03
- **Recipient organization:** SAINT LOUIS UNIVERSITY
- **Principal Investigator:** Sofia Origanti
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $318,150
- **Award type:** 5
- **Project period:** 2022-07-07 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10832675

## Citation

> US National Institutes of Health, RePORTER application 10832675, Mechanism and Regulation of eIF6 in Translation (5R01GM143179-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10832675. Licensed CC0.

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