# Mechanisms and regulation of localized mRNA translation

> **NIH NIH F32** · DUKE UNIVERSITY · 2020 · $64,926

## Abstract

ABSTRACT
RNA localization is an evolutionarily conserved mechanism for the spatiotemporal regulation of protein
synthesis. Secretory and membrane protein-encoding mRNAs are the largest cohort of localized mRNAs,
comprising approximately 35% of protein-encoding genes, and are thought to undergo co-translational
localization to the endoplasmic reticulum (ER) via the signal recognition particle (SRP) pathway. While SRP
pathway function in protein translocation is well accepted, a companion role in mRNA localization on the ER
has not been established. Strikingly, recent studies revealed that all mRNAs can be locally translated on the
ER, indicating an unexpected diversity in ER-localized gene expression and suggesting that multiple, though
as yet unknown, pathways function in RNA localization to the ER. To this end, work from our lab and others
have provided new evidence that RNA binding proteins (RBPs) contribute key functions in mRNA localization
to the ER. However, our understanding of how RBPs mediate mRNA transport to the ER for regulated
translation is very limited. Here, we propose to uncover the molecular mechanisms of ER-specific mRNA
regulation by RBPs, using leucine-rich repeat containing 59 (LRRC59) as a model. LRRC59 is a highly
conserved and constitutively expressed ER-resident protein known to bind the ribosome and RNA. Using
proximity proteomics, we recently discovered that LRRC59 also interacts with SRP factors and translation
machinery. From these data, we hypothesize that LRRC59 functions in compartmentalized mRNA
regulation by anchoring target mRNAs and ribosomes in close proximity to facilitate efficient protein
synthesis. To test this hypothesis, we will combine advanced deep sequencing approaches with optimized
subcellular fractionation methods on wild type and LRRC59 knockout models to: (1) identify the LRRC59-
associated RNA transcriptome, and (2) investigate the molecular mechanism of LRRC59-regulated translation
on the ER. Given the importance of ER stress and translational re-programming on human health, we further
hypothesize that LRRC59 may have a role in maintaining cellular proteostasis. Using transcriptome-wide
sequencing approaches and optical imaging technologies, we will be able to address how ER translation is
regulated during ER stress, both globally and in a LRRC59-specific manner. Collectively, we expect this work
to reveal new mechanisms that govern compartmentalized mRNA localization and translation in normal human
physiology and disease. Importantly, the proposed studies will enhance my training in multiple aspects
of RNA biology and RNA-related technologies, and provide me with the necessary foundation to build
an independent research program.

## Key facts

- **NIH application ID:** 10066080
- **Project number:** 1F32GM139254-01
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Molly Marie Hannigan
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $64,926
- **Award type:** 1
- **Project period:** 2020-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10066080

## Citation

> US National Institutes of Health, RePORTER application 10066080, Mechanisms and regulation of localized mRNA translation (1F32GM139254-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10066080. Licensed CC0.

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