PUBLICATION

Direct lysine dimethylation of IRF3 by the methyltransferase SMYD3 attenuates antiviral innate immunity

Authors
Wang, Z., Chen, X., Zhu, C., Fan, S., Tang, J., Deng, H., Sun, X., Liu, X., Xiao, W.
ID
ZDB-PUB-250116-1
Date
2025
Source
Proceedings of the National Academy of Sciences of the United States of America   122: e2320644122e2320644122 (Journal)
Registered Authors
Xiao, Wuhan
Keywords
IRF3, SMYD3, innate immunity, methylation
MeSH Terms
  • Signal Transduction/immunology
  • Lysine*/metabolism
  • Phosphorylation
  • Histone-Lysine N-Methyltransferase*/genetics
  • Histone-Lysine N-Methyltransferase*/metabolism
  • Interferon Type I/immunology
  • Interferon Type I/metabolism
  • Mice, Knockout
  • Immunity, Innate*
  • HEK293 Cells
  • Humans
  • Animals
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/immunology
  • Zebrafish Proteins/metabolism
  • Mice
  • Zebrafish*/immunology
  • Interferon Regulatory Factor-3*/metabolism
  • Methylation
PubMed
39813248 Full text @ Proc. Natl. Acad. Sci. USA
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.
Genes / Markers
Figures
Show all Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping