# Understanding the OAS/RNase L pathway during pathogenic viral infections

> **NIH NIH R35** · UNIVERSITY OF FLORIDA · 2023 · $483,000

## Abstract

PROJECT SUMMARY
 Ribonuclease L (RNase L) is a key component of the mammalian innate antiviral response. For decades, RNase
L was presumed to reduce viral protein synthesis by cleaving ribosomes to arrest translation. However, we and others
recently demonstrated that RNase L-cleaved ribosomes are translation-competent, and that pathogenic viruses can
synthesize proteins despite activating RNase L. These observations have revealed a significant gap in knowledge
regarding how RNase L functions and how viruses evade it. We have demonstrated that RNase L rapidly degrades nearly
all cellular mRNAs upon activation. This activity regulates three cellular processes that have expanded our understanding
of RNase L and that have elucidated how pathogenic viruses evade and potentially hijack RNase L functions. First,
RNase L reprograms translation to an antiviral state by degrading constitutively expressed cellular mRNAs while
sparing host mRNAs encoding antiviral proteins (e.g., type I interferons), which permits antiviral protein synthesis.
Importantly, the mRNAs encoded by several pathogenic viruses (e.g., dengue virus) similarly evade RNase L-mediated
mRNA decay, thus permitting viral protein synthesis. This observation has elucidated how pathogenic viruses synthesize
proteins despite activating RNase L. This application proposes to characterize the RNase L-mediated mRNA decay
pathway and determine how host and viral mRNAs evade it. Second, RNase L activation triggers the inhibition of nuclear
mRNA export. This is a critical antiviral mechanism that antagonizes influenza A virus protein synthesis, but it also
downregulates the expression of host antiviral proteins (e.g., type I interferons). Importantly, pathogenic viruses (e.g.,
dengue virus) activate this RNase L-dependent pathway, resulting in sequestration of host antiviral mRNAs in the
nucleus. This observation suggests that viruses potentially hijack this function of RNase L to limit host antiviral protein
production. This application aims to determine how RNase L inhibits mRNA export, the breadth of viruses it antagonizes,
how it impacts host antiviral gene expression during pathogenic viral infections. Third, RNase L regulates the assembly
of cytoplasmic antiviral ribonucleoprotein complexes. Specifically, RNase L inhibits the assembly of stress granules and
promotes the assembly of an alternative stress granule-like ribonucleoprotein complex termed RNase L-dependent body.
RNase L-dependent bodies are the predominant antiviral granule assembled in response to SARS-CoV-2 or dengue virus
infection, yet their function is completely unknown. This application aims to determine the function of antiviral stress
granules and RNase L-dependent bodies and to determine how their regulation by RNase L alters the antiviral response.
Understanding the mechanisms and functions of these cellular processes will advance our understanding of the
OAS/RNase L pathway, innate immune antiviral gene induction, and virol...

## Key facts

- **NIH application ID:** 10714902
- **Project number:** 1R35GM151249-01
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** James M Burke
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $483,000
- **Award type:** 1
- **Project period:** 2023-09-15 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10714902

## Citation

> US National Institutes of Health, RePORTER application 10714902, Understanding the OAS/RNase L pathway during pathogenic viral infections (1R35GM151249-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10714902. Licensed CC0.

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