PTK2B promotes TBK1 and STING oligomerization and enhances the STING-TBK1 signaling

Yongfang Lin, Jing Yang, Qili Yang, Sha Zeng, Jiayu Zhang, Yuanxiang Zhu, Yuxin Tong, Lin Li, Weiqi Tan, Dahua Chen () and Qinmiao Sun ()
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Yongfang Lin: State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences
Jing Yang: State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences
Qili Yang: State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences
Sha Zeng: Yunnan University
Jiayu Zhang: State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences
Yuanxiang Zhu: Yunnan University
Yuxin Tong: Yunnan University
Lin Li: State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences
Weiqi Tan: State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences
Dahua Chen: Yunnan University
Qinmiao Sun: State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract TANK-binding kinase 1 (TBK1) is a key kinase in regulating antiviral innate immune responses. While the oligomerization of TBK1 is critical for its full activation, the molecular mechanism of how TBK1 forms oligomers remains unclear. Here, we show that protein tyrosine kinase 2 beta (PTK2B) acts as a TBK1-interacting protein and regulates TBK1 oligomerization. Functional assays reveal that PTK2B depletion reduces antiviral signaling in mouse embryonic fibroblasts, macrophages and dendritic cells, and genetic experiments show that Ptk2b-deficient mice are more susceptible to viral infection than control mice. Mechanistically, we demonstrate that PTK2B directly phosphorylates residue Tyr591 of TBK1, which increases TBK1 oligomerization and activation. In addition, we find that PTK2B also interacts with the stimulator of interferon genes (STING) and can promote its oligomerization in a kinase-independent manner. Collectively, PTK2B enhances the oligomerization of TBK1 and STING via different mechanisms, subsequently regulating STING-TBK1 activation to ensure efficient antiviral innate immune responses.

Date: 2023
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DOI: 10.1038/s41467-023-43419-4

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