# Translation control of stress response and innate immunity

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2021 · $340,793

## Abstract

Project Summary
The long-term goal of this project is to understand how mRNA translational regulatory mechanisms control
cellular stress response under physiological and pathological conditions. The specific pathway of interest is the
Integrated Stress Response (ISR), which involves stress-responsive kinases that phosphorylate the α subunit of
eIF2 to attenuate general translational initiation. More recently, we discovered that ISR inhibits mRNA translation
through the induction of yet another translational inhibitor 4E-BP. At the same time, such conditions
paradoxically stimulate the translation of transcription factors such as ATF4, due to the presence of regulatory
upstream Open Reading Frames (uORFs) that precede the main ATF4 ORF. How stress responsive transcripts
evade translational inhibition, or even undergo more active expression, in stressed cells is one of the major
conceptual questions that remains poorly understood. Our preliminary studies using Drosophila have led us to a
number of new insights to this question: These include our findings that (1) ISR boosts innate immune response
to bacterial infection and anti-microbial peptides have 5’UTRs that can evade translational inhibition imposed by
ISR signaling, (2) that previously unexpected factors regulate the activation of ISR, and (3) that ATF6 also has a
5’UTR that stimulates the main ORF translation in response to stress. Here I propose to use Drosophila to
investigate the underlying regulatory mechanisms and determine how the newly identified ISR regulatory factors
affect innate immune response, inflammation, and lifespan of Drosophila. We will supplement the molecular
genetics-based approach with genomic tools such as ribosome profiling and structure-based modeling studies.
Three Specific Aims will be pursued: (1) We will determine how ISR signaling enhances innate immune
response, mainly focusing on the idea that anti-microbial peptide transcripts undergo mRNA translation through
an unconventional mechanism to evade translational inhibition associated with ISR signaling. (2) Through the
characterization of the novel ISR regulators that we have identified, we plan to determine how uORF containing
transcripts increase their translation when general mRNA translation is suppressed, and examine how they
affect phenotypes associated with abnormal ISR regulation. (3) We will test the hypothesis that ATF6 is another
transcription factor that is regulated at the level of mRNA translation during ISR to mediate its transcriptional
response. Notably, impairment or excessive stimulation of this pathway underlies various neurodegenerative
and metabolic disorders in humans. Therefore, a better understanding of the regulatory mechanisms will not only
advance our conceptual understanding of gene expression regulation in cells under stress but also may prompt
the development of new strategies to modulate ISR signaling for therapeutic purposes.

## Key facts

- **NIH application ID:** 10236328
- **Project number:** 5R01GM125954-04
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** HYUNG D RYOO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $340,793
- **Award type:** 5
- **Project period:** 2018-09-20 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10236328

## Citation

> US National Institutes of Health, RePORTER application 10236328, Translation control of stress response and innate immunity (5R01GM125954-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10236328. Licensed CC0.

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