# Structural Regulation of IRF3 Activation and Association with Co-activators of the IFN Beta Enhanceosome

> **NIH NIH F31** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2020 · $29,215

## Abstract

PROJECT SUMMARY
Following exposure to a virus, the immune system activates and takes rapid measures to protect the body from
a spreading infection. Our understanding of the signaling cascade that leads to immuno-activation in response
to viral infections is crucial for designing efficient therapeutic drugs that regulate this process. Cell surface and
cytosolic receptors recognize pathogen-specific molecules such as viral nucleic acids that activate the
interferon regulator factors 3 (IRF3), which is a master regulator of immune activation. Once activated, IRF3
promotes the expression of interferon β (IFNβ), which is essential for the antiviral response. Despite IRF3's
active role in antiviral response, dysregulation in IRF3 expression has been implicated in multiple autoimmune
diseases. Strict regulation of IFNβ is critical to minimize uncontrolled inflammation damage to infected hosts
while clearing the infection. Together with ATF2/c-Jun, p65/p50, and IRF7, IRF3 form a higher order molecular
complex called the IFNβ enhanceosome to strictly regulate IFNβ expression. While the principles of the
signaling pathway that activates IRF3 and induces IFNβ expression are established, structural insights into the
activation of IRF3 and IFNβ enhanceosome assembly remain scarce. In this proposal, I seek to characterize
the structural mechanism of IRF3 activation by using X-ray crystallography. Then, I will use cryo-electron
microscopy to characterize the structural features promoting IRF3 interactions with p65 at the enhanceosome.
These studies will provide insights into how the other IRFs get activated and how other enhanceosome
complexes assemble. Most importantly, structural-based analyses of IRF3 activation and assembly with p65
will provide a basis for designing small molecule modulators that can directly target the activation and
suppression of IRF3 in response to viral infections and autoimmune diseases, respectively.
!

## Key facts

- **NIH application ID:** 10208463
- **Project number:** 3F31GM129988-02S1
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Anne Jecrois
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $29,215
- **Award type:** 3
- **Project period:** 2018-08-01 → 2021-07-16

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10208463

## Citation

> US National Institutes of Health, RePORTER application 10208463, Structural Regulation of IRF3 Activation and Association with Co-activators of the IFN Beta Enhanceosome (3F31GM129988-02S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10208463. Licensed CC0.

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