# The splicing factor CELF2 suppresses RNA ligands sensed by RIG-I-like receptor

> **NIH NIH R21** · UNIVERSITY OF WASHINGTON · 2024 · $220,625

## Abstract

Project Summary
The goal of this proposal is to investigate a novel role of CELF2 in suppressing interferon responses to self-
RNA ligands. While interferons (IFN) induced by non-self-viral RNA activate an antiviral program to restrict viral
pathogens, their aberrant expression can cause tissue damage leading to autoimmunity. Although the toll-like
receptors and RIG-I-like receptors normally sense non-self RNA, these sensors are also activated by self-RNA
under certain conditions. Recognition of self-RNA can be a consequence of a failure of the suppression of the
self-RNA ligands. RNA editing by ADAR1 is one pathway used to suppress self-RNA ligands, but it is
conceivable that there are many other mechanisms that suppress endogenous immunostimulatory RNA
ligands. We made a surprising observation that the loss of splicing factor CELF2 induced a robust induction of
type I IFN and IFN-stimulated genes. Splicing factors are required for mRNA processing and post-
transcriptional regulation, however the effect of aberrant and alternative splicing on IFN responses is
understudied. We found that IFN induced during CELF2 depletion is dependent on RIG-I-like receptors. In this
proposal, we will identify the mechanisms of CELF2-mediated suppression of IFN activation. CELF2 has not
been previously implicated in suppressing immunostimulatory self-RNA ligands. This study will describe a
novel role for CELF2 in innate immune signaling, but also study the effect of perturbation of mRNA splicing on
innate immunity. This study has the potential to uncover mechanisms of the biogenesis of endogenous RNA
that activates the RLR pathway. These findings could have a significant impact on understanding IFN-induced
immune pathologies and identify new therapeutic targets in autoimmunity.

## Key facts

- **NIH application ID:** 10772162
- **Project number:** 5R21AI176442-02
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Ram Savan
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $220,625
- **Award type:** 5
- **Project period:** 2023-02-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10772162

## Citation

> US National Institutes of Health, RePORTER application 10772162, The splicing factor CELF2 suppresses RNA ligands sensed by RIG-I-like receptor (5R21AI176442-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10772162. Licensed CC0.

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