2. Academic Validation
  3. Asparagine sensing by TBK1 controls its phase separation to drive antiviral innate immune responses

Asparagine sensing by TBK1 controls its phase separation to drive antiviral innate immune responses

  • Mol Cell. 2026 Feb 19;86(4):722-739.e8. doi: 10.1016/j.molcel.2026.01.010.
Jie Du 1,  Chaoqun Li 1,  Li Chai 1,  Fabao Zhao 2,  Lin Lv 3,  Zongcheng Yang 4,  Zhiyuan Zhao 1,  Rong Gong 1,  Liu Yang 1,  Meng Wu 5,  Meng Nie 6,  Jihui Jia 3,  Dongwei Kang 2,  Chengjiang Gao 1,  Wei Zhao 3,  Mutian Jia 7
Affiliations

Affiliations

  • 1 Key Laboratory of Infection and Immunity of Shandong Province and Department of Immunology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong, China.
  • 2 Key Laboratory of Chemical Biology (Ministry of Education) and Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong, China.
  • 3 Key Laboratory of Infection and Immunity of Shandong Province and Department of Pathogenic Biology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong, China.
  • 4 The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, Anhui, China.
  • 5 Department of Cell Biology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong, China.
  • 6 School of Public Health, Capital Medical University, Beijing 100069, China.
  • 7 Key Laboratory of Infection and Immunity of Shandong Province and Department of Immunology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong, China; State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shandong University, Jinan 250012, Shandong, China. Electronic address: [email protected].
PMID: 41653919 DOI: 10.1016/j.molcel.2026.01.010
Abstract

Competition between the host and invading viruses for cellular nutrients determines the outcomes of infectious diseases. Nutrients are increasingly being recognized as regulators that interact with immunological signals, but how immune cells sense specific nutrients to regulate Antiviral innate immune responses remains elusive. Here, we establish asparagine (Asn) as an intercellular nutritional checkpoint that is sensed by TANK-binding kinase 1 (TBK1) to drive innate immune responses in human and murine cells. Mechanistically, Asn directly binds to TBK1, which robustly induces TBK1 phase separation and forms liquid-like droplets, promoting TBK1 transautophosphorylation and activation. Moreover, viral Infection reduces asparagine synthetase (ASNS) expression to establish an Asn-restricted microenvironment, thereby evading TBK1-triggered host immune defenses. Overall, our results suggest that TBK1 is a natural Asn sensor that links host nutritional homeostasis to Antiviral immune responses and reveal that targeting Asn availability is a promising therapeutic strategy for diseases involving dysregulated TBK1 activation.

Keywords

IFN responses; TBK1; asparagine; phase separation; virus infection.

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