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<p>The precise control of type I interferon (IFN-I) signaling is critical for effective antiviral defense and the maintenance of immune balance. In this study, we revealed a dynamic regulatory network involving lactylation–delactylation of TANK binding kinase 1 (TBK1), a pivotal kinase of IFN-I signaling, that finely tunes antiviral immune responses. Viral infection triggers the lactylation of TBK1 at K241, which is mediated by alanyl-tRNA synthetase 1 (AARS1), which potentiates IFN-I signaling to establish an antiviral state. Notably, we identified sirtuin 6 (SIRT6) as a pivotal “eraser” responsible for reversing this process by removing TBK1 lactylation. This action initiates a stringent negative feedback loop, leading to delactylated TBK1 being targeted by the E3 ligase SIAH2 for K48-linked polyubiquitination and subsequent selective autophagic degradation via p62. In vivo experiments revealed that myeloid-specific deletion of <i>Sirt6</i> in mice resulted in sustained TBK1 lactylation and increased IFN-I production during VSV infection, ultimately improving survival. This intricate regulatory circuit not only maintains an appropriate IFN-I response to prevent excessive immune activation but also highlights the potential of targeting lactylation as a novel therapeutic strategy for chronic infections and autoimmune diseases associated with TBK1 dysregulation.</p>

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Dynamic regulation of TBK1 lactylation shapes antiviral immune responses

  • 期刊论文

  • 发表日期：

    2026年1月13日

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  • Yingchao Xie,
  • Yufen Zhang,
  • Wenqiang Peng,
  • Liying Zhang,
  • Zhiqiang Hu,
  • Huaji Jiang,
  • Ke Zeng,
  • Jiansen Lu,
  • Shuping Tan,
  • Zhongxin Han,
  • Zilong Xiao,
  • Zijun Liu,
  • Weiwei Liu,
  • Xiao Yu

摘要

The precise control of type I interferon (IFN-I) signaling is critical for effective antiviral defense and the maintenance of immune balance. In this study, we revealed a dynamic regulatory network involving lactylation–delactylation of TANK binding kinase 1 (TBK1), a pivotal kinase of IFN-I signaling, that finely tunes antiviral immune responses. Viral infection triggers the lactylation of TBK1 at K241, which is mediated by alanyl-tRNA synthetase 1 (AARS1), which potentiates IFN-I signaling to establish an antiviral state. Notably, we identified sirtuin 6 (SIRT6) as a pivotal “eraser” responsible for reversing this process by removing TBK1 lactylation. This action initiates a stringent negative feedback loop, leading to delactylated TBK1 being targeted by the E3 ligase SIAH2 for K48-linked polyubiquitination and subsequent selective autophagic degradation via p62. In vivo experiments revealed that myeloid-specific deletion of Sirt6 in mice resulted in sustained TBK1 lactylation and increased IFN-I production during VSV infection, ultimately improving survival. This intricate regulatory circuit not only maintains an appropriate IFN-I response to prevent excessive immune activation but also highlights the potential of targeting lactylation as a novel therapeutic strategy for chronic infections and autoimmune diseases associated with TBK1 dysregulation.