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<p>The transcription factor interferon regulatory factor 3 (IRF3) initiates type I interferon transcription, which is required for host defense. Here, we identify RAD18 as a central E3 ubiquitin ligase that selectively targets phosphorylated IRF3 (p-IRF3) for autophagic degradation. RAD18 specifically promotes the dissociation of p-IRF3 from the <i>IFNB</i> promoter and in turn terminates its transcriptional activity. Mechanistically, RAD18 binds the p-IRF3 dimer located on the <i>IFNB</i> promoter and triggers K63 polyubiquitylation of p-IRF3 at Lys 193. The ubiquitylated p-IRF3 dimer consequently dissociates from the <i>IFNB</i> promoter, translocates out of the nucleus and undergoes OPTN-mediated autophagic degradation. <i>Rad18</i><sup>fl/fl</sup> <i>Lysm-cre</i> mice resist lethal vesicular stomatitis virus infection in vivo due to IFNβ overproduction. In H1N1-infected human macrophages or monocytes from individuals with active systemic lupus erythematosus, RAD18 protein levels negatively correlate with p-IRF3 and <i>IFNB1</i> mRNA levels. Thus, RAD18 functions as a break to terminate IRF3-driven <i>IFNB1</i> transcription and may be a potential therapeutic target for RNA virus infection or autoimmune diseases.</p>

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E3 ligase RAD18 targets phosphorylated IRF3 to terminate IFNB1 transcription

  • 期刊论文

  • 发表日期：

    2025年8月29日

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  • Yiting Cai,
  • Jiaqi Zheng,
  • Linlin Zhao,
  • Xue Wang,
  • Lu Zhang,
  • Jun Wang,
  • Yuchuan Zhang,
  • Rui Shi,
  • Jin Han,
  • Wei Han,
  • Wei Chen

摘要

The transcription factor interferon regulatory factor 3 (IRF3) initiates type I interferon transcription, which is required for host defense. Here, we identify RAD18 as a central E3 ubiquitin ligase that selectively targets phosphorylated IRF3 (p-IRF3) for autophagic degradation. RAD18 specifically promotes the dissociation of p-IRF3 from the IFNB promoter and in turn terminates its transcriptional activity. Mechanistically, RAD18 binds the p-IRF3 dimer located on the IFNB promoter and triggers K63 polyubiquitylation of p-IRF3 at Lys 193. The ubiquitylated p-IRF3 dimer consequently dissociates from the IFNB promoter, translocates out of the nucleus and undergoes OPTN-mediated autophagic degradation. Rad18fl/fl Lysm-cre mice resist lethal vesicular stomatitis virus infection in vivo due to IFNβ overproduction. In H1N1-infected human macrophages or monocytes from individuals with active systemic lupus erythematosus, RAD18 protein levels negatively correlate with p-IRF3 and IFNB1 mRNA levels. Thus, RAD18 functions as a break to terminate IRF3-driven IFNB1 transcription and may be a potential therapeutic target for RNA virus infection or autoimmune diseases.