2. Academic Validation
  3. Dynamic regulation of TBK1 lactylation shapes antiviral immune responses

Dynamic regulation of TBK1 lactylation shapes antiviral immune responses

  • Cell Mol Immunol. 2026 Mar;23(3):284-300. doi: 10.1038/s41423-025-01385-5.
Yingchao Xie # 1,  Yufen Zhang # 1,  Wenqiang Peng # 1,  Liying Zhang 1,  Zhiqiang Hu 1 2,  Huaji Jiang 1 3,  Ke Zeng 1 4,  Jiansen Lu 1 4,  Shuping Tan 1 5,  Zhongxin Han 1,  Zilong Xiao 1,  Zijun Liu 1,  Weiwei Liu 1,  Xiao Yu 6 7 8
Affiliations

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.
  • 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.
  • 3 Department of Pain and Traditional Medicine Orthopedics, Yue Bei People's Hospital Affiliated to Shantou University Medical College, Shaoguan, China.
  • 4 Department of Joint Surgery, Shaoguan First People's Hospital, Affiliated Hospital of Shaoguan University, Shaoguan, China.
  • 5 Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
  • 6 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. [email protected].
  • 7 Guangdong Provincial Key Laboratory of Single-cell and Extracellular Vesicles, Southern Medical University, Guangzhou, China. [email protected].
  • 8 State Key Laboratory of Multi-organ Injury Prevention and Treatment, Southern Medical University, Guangzhou, China. [email protected].
  • # Contributed equally.
PMID: 41530535 DOI: 10.1038/s41423-025-01385-5
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.

Keywords

Lactylation; Palmitoylation; Sirtuin 6 (SIRT6); TANK binding kinase 1 (TBK1); Type I interferon (IFN-I).

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