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Updated: Jun 2, 2025
A High Resolution Method to Monitor Phosphorylation-dependent Activation of IRF3
Published on: January 24, 2016
Direct lysine dimethylation of IRF3 by the methyltransferase SMYD3 attenuates antiviral innate immunity
Zixuan Wang1,2,3,4,5, Xiaoyun Chen1,2,3,4,5, Chunchun Zhu1,2,3,4,5
1Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430070, People's Republic of China.
Abstract:
Interferon regulatory factor 3 (IRF3) is the key transcription factor in the type I IFN signaling pathway, whose activation is regulated by multiple posttranslational modifications. Here, we identify SMYD3, a lysine methyltransferase, as a negative regulator of IRF3. SMYD3 interacts with IRF3 and catalyzes the dimethylation of IRF3 at lysine 39. This modification reduces IRF3 phosphorylation, dimerization, and subsequent nuclear translocation, leading to the inhibition of downstream type I interferon production. In addition, Smyd3-deficient mice are more resistant to RNA and DNA viral infections. Zebrafish lacking smyd3 or treated with the inhibitor BCI121 are also more resistant to viral infection. Our findings reveal a role for SMYD3 in the regulation of antiviral innate immunity and provide insight into a specific modulation of IRF3 that affects its activation.
Insights
SMYD3, a lysine methyltransferase, negatively regulates Interferon Regulatory Factor 3 (IRF3) activation. This finding reveals SMYD3
Area of Science:
- Immunology
- Molecular Biology
- Virology
Background:
- Type I interferon (IFN) signaling is crucial for antiviral innate immunity.
- Activation of the key transcription factor Interferon Regulatory Factor 3 (IRF3) is tightly regulated by posttranslational modifications.
Purpose of the Study:
- To identify novel regulators of IRF3 activation.
- To elucidate the role of SMYD3 in the type I IFN signaling pathway and antiviral immunity.
Main Methods:
- Biochemical assays to detect protein interactions and posttranslational modifications.
- Analysis of IRF3 phosphorylation, dimerization, and nuclear translocation.
- In vivo studies using Smyd3-deficient mice and zebrafish models of viral infection.
Main Results:
- SMYD3, a lysine methyltransferase, was identified as a negative regulator of IRF3.
- SMYD3 catalyzes dimethylation of IRF3 at lysine 39, inhibiting its phosphorylation and activation.
- Smyd3 deficiency or inhibition enhances resistance to viral infections in mice and zebrafish.
Conclusions:
- SMYD3 plays a significant role in negatively regulating antiviral innate immunity by modulating IRF3 activation.
- Targeting SMYD3 may represent a therapeutic strategy to enhance antiviral responses.
