2. Academic Validation
  3. Teleost-specific TLR25/MyD88 signaling promotes K63-linked ubiquitination of IRF1 to induce IFNa gene expression

Teleost-specific TLR25/MyD88 signaling promotes K63-linked ubiquitination of IRF1 to induce IFNa gene expression

  • Fish Shellfish Immunol. 2025 Aug 19:166:110672. doi: 10.1016/j.fsi.2025.110672.
Yunkun Li 1,  Shihui Yi 2,  Wuhao Tang 2,  Lei Shi 2,  Huizhen Yan 2,  Lei Ning 2,  Jing Pu 2,  Kanbei Shiyi 2,  Lanxin Zhang 2,  Xiaoshuang Chen 2,  Jiayun Wu 3,  Shiyong Yang 4,  Xianyin Zeng 5,  Xiaogang Du 6
Affiliations

Affiliations

  • 1 Department of Engineering and Applied Biology, College of Life Science, Sichuan Agricultural University, Ya'an, 625014, Sichuan, PR China. Electronic address: yunkun.li@sicau.edu.cn.
  • 2 Department of Engineering and Applied Biology, College of Life Science, Sichuan Agricultural University, Ya'an, 625014, Sichuan, PR China.
  • 3 Department of Zoology, College of Life Science, Sichuan Agricultural University, Ya'an, 625014, Sichuan, PR China.
  • 4 Department of Aquaculture, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, 611130, Sichuan, PR China; Aquatic Health and Intelligent Aquaculture Key Laboratory of Sichuan Province, Chengdu, 611130, Sichuan, PR China.
  • 5 Department of Engineering and Applied Biology, College of Life Science, Sichuan Agricultural University, Ya'an, 625014, Sichuan, PR China. Electronic address: xyzeng@sicau.edu.cn.
  • 6 Department of Engineering and Applied Biology, College of Life Science, Sichuan Agricultural University, Ya'an, 625014, Sichuan, PR China. Electronic address: duxiaogang@sicau.edu.cn.
PMID: 40840666 DOI: 10.1016/j.fsi.2025.110672
Abstract

Interferon regulatory factor 1 (IRF1) serves as the primary transcription factor responsible for inducing interferon a (IFNa) gene expression in teleost fish. While mammalian IRF1 is known to be unstable due to ubiquitin-mediated degradation, its function critically dependents on stability regulation by upstream signals. However, the mechanisms governing the protein stability of IRF1 remain unexplored in teleost fish. In this study, we identified IRF1 from ya-fish (Schizothorax prenanti) and demonstrated its specific role in activating IFNa transcription. Notably, teleost-specific Toll-like Receptor 25 (TLR25) enhances IRF1 protein stability through the direct recruitment of the adaptor MyD88, thereby facilitating IFNa gene expression. The death domain (DD) and intermediate domain (IM) of MyD88 are essential for this stabilization. IRF1 undergoes both K48- and K63-linked ubiquitination modifications, which exhibit competitive antagonism. The TLR25/MyD88 signaling promotes both types of ubiquitination but preferentially amplifies K63-linked ubiquitination over K48-linked ubiquitination. Furthermore, this enhancement relies on TLR25/MyD88-driven activation of NF-κB inflammatory pathway. Our findings contribute to the understanding of how fish regulate IRF1 protein stability to increase IFNa gene expression during pathogen invasions.

Keywords

Fish; IFNa; IRF1; TLR25; Ubiquitination.

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