PTK2B promotes TBK1 and STING oligomerization and enhances the STING-TBK1 signaling
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)...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-11-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-43419-4 |
| _version_ | 1827633742266499072 |
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| author | Yongfang Lin Jing Yang Qili Yang Sha Zeng Jiayu Zhang Yuanxiang Zhu Yuxin Tong Lin Li Weiqi Tan Dahua Chen Qinmiao Sun |
| author_facet | Yongfang Lin Jing Yang Qili Yang Sha Zeng Jiayu Zhang Yuanxiang Zhu Yuxin Tong Lin Li Weiqi Tan Dahua Chen Qinmiao Sun |
| author_sort | Yongfang Lin |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T15:03:45Z |
| format | Article |
| id | doaj.art-2fb52ff393414802a7ab89ccd4640b88 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-09T15:03:45Z |
| publishDate | 2023-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-2fb52ff393414802a7ab89ccd4640b882023-11-26T13:45:19ZengNature PortfolioNature Communications2041-17232023-11-0114111710.1038/s41467-023-43419-4PTK2B promotes TBK1 and STING oligomerization and enhances the STING-TBK1 signalingYongfang Lin0Jing Yang1Qili Yang2Sha Zeng3Jiayu Zhang4Yuanxiang Zhu5Yuxin Tong6Lin Li7Weiqi Tan8Dahua Chen9Qinmiao Sun10State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of SciencesState Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of SciencesState Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of SciencesInstitute of Biomedical Research, Yunnan UniversityState Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of SciencesInstitute of Biomedical Research, Yunnan UniversityInstitute of Biomedical Research, Yunnan UniversityState Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of SciencesState Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of SciencesInstitute of Biomedical Research, Yunnan UniversityState Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of SciencesAbstract 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.https://doi.org/10.1038/s41467-023-43419-4 |
| spellingShingle | Yongfang Lin Jing Yang Qili Yang Sha Zeng Jiayu Zhang Yuanxiang Zhu Yuxin Tong Lin Li Weiqi Tan Dahua Chen Qinmiao Sun PTK2B promotes TBK1 and STING oligomerization and enhances the STING-TBK1 signaling Nature Communications |
| title | PTK2B promotes TBK1 and STING oligomerization and enhances the STING-TBK1 signaling |
| title_full | PTK2B promotes TBK1 and STING oligomerization and enhances the STING-TBK1 signaling |
| title_fullStr | PTK2B promotes TBK1 and STING oligomerization and enhances the STING-TBK1 signaling |
| title_full_unstemmed | PTK2B promotes TBK1 and STING oligomerization and enhances the STING-TBK1 signaling |
| title_short | PTK2B promotes TBK1 and STING oligomerization and enhances the STING-TBK1 signaling |
| title_sort | ptk2b promotes tbk1 and sting oligomerization and enhances the sting tbk1 signaling |
| url | https://doi.org/10.1038/s41467-023-43419-4 |
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