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Dynamic regulation of TBK1 lactylation shapes antiviral immune responses

Cellular & Molecular Immunology (2026)Cite this article

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Abstract

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.

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Acknowledgements

We thank Professor Jun Cui (Sun Yat-sen University) for providing plasmids for NDP52, OPTN, NIX, TOLLIP, NBR1, and autophagy-related KO cells. This work was supported by the National Natural Science Foundation of China (82572009, 82371761 and 82171741), the National Key R&D Program of China (2024YFC2309700), the Guangdong Basic and Applied Basic Research Foundation (2023A1515010421), and the Science and Technology Program of Guangzhou (2025A04J7166) to XY.

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  1. These authors contributed equally: Yingchao Xie, Yufen Zhang, Wenqiang Peng.

Authors and Affiliations

  1. Department of Immunology, School of Basic Medical Sciences, Department of Clinical Laboratory Medicine, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China

    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

  2. Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China

    Zhiqiang Hu

  3. Department of Pain and Traditional Medicine Orthopedics, Yue Bei People’s Hospital Affiliated to Shantou University Medical College, Shaoguan, China

    Huaji Jiang

  4. Department of Joint Surgery, Shaoguan First People’s Hospital, Affiliated Hospital of Shaoguan University, Shaoguan, China

    Ke Zeng & Jiansen Lu

  5. Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China

    Shuping Tan

  6. Guangdong Provincial Key Laboratory of Single-cell and Extracellular Vesicles, Southern Medical University, Guangzhou, China

    Xiao Yu

  7. State Key Laboratory of Multi-organ Injury Prevention and Treatment, Southern Medical University, Guangzhou, China

    Xiao Yu

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Contributions

YX, YZ and WP performed the investigation and the analysis. LZ, ZHu, HJ, KZ, JL, ST, ZHan, ZX, ZL and WL provided technical help. XY provided resources, conceived the idea, and directed the research. YX and XY wrote the manuscript.

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Correspondence to Xiao Yu.

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Xie, Y., Zhang, Y., Peng, W. et al. Dynamic regulation of TBK1 lactylation shapes antiviral immune responses. Cell Mol Immunol (2026). https://doi.org/10.1038/s41423-025-01385-5

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