TBKBP1 and TBK1 form a growth factor signalling axis mediating immunosuppression and tumourigenesis
Open accessAbstract
TANK-binding kinase 1 (TBK1) responds to microbial stimuli and mediates the induction of type I interferon (IFN). Here, we show that TBK1 is also a central mediator of growth factor signalling; this function of TBK1 relies on a specific adaptor-TBK-binding protein 1 (TBKBP1). TBKBP1 recruits TBK1 to protein kinase C-theta (PKCθ) through a scaffold protein, CARD10. This enables PKCθ to phosphorylate TBK1 at Ser 716, a crucial step for TBK1 activation by growth factors but not by innate immune stimuli. Although the TBK1-TBKBP1 signalling axis is not required for the induction of type I IFN, it mediates mTORC1 activation and oncogenesis. Conditional deletion of either TBK1 or TBKBP1 in lung epithelial cells inhibits tumourigenesis in a mouse model of lung cancer. In addition to promoting tumour growth, the TBK1-TBKBP1 axis facilitates tumour-mediated immunosuppression through a mechanism that involves induction of the checkpoint molecule PD-L1 and stimulation of glycolysis. These findings suggest a PKCθ-TBKBP1-TBK1 growth factor signalling axis that mediates both tumour growth and immunosuppression.
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Disrupting TBK1 signaling has shown early promise enhancing response to ICB in murine tumour models.
“and that disrupting TBK1 signaling has shown early promise enhancing response to ICB in murine tumour models 14,15 .”
From Targeting TBK1 to overcome resistance to cancer immunotherapy (2023) · cites this paper as [15]
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References 58 · Cited by 109
- Authors
- Zhu, L., Li, Y., Xie, X., Zhou, X., Gu, M., Jie, Z., Ko, C.-J., Gao, T., Hernandez, B. E., Cheng, X., & Sun, S.-C.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Corresponding author
- Sun, Shao-Cong
- ORCID
- Venue
- Nature Cell Biology
- Published
- 2019-12
- Volume
- 21
- Issue
- 12
- Pages
- 1604-1614
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- PMC
- PMC6901116
- OpenAlex
- W2991240508
- Cited by
- 109
- References
- 58
- Citations by year
- 2026: 10 · 2025: 13 · 2024: 19 · 2023: 13 · 2022: 32 · 2021: 14 · 2020: 8
- FWCI
- 4.47
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases (AI057555)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Keywords
- TBK1, protein kinase C theta, CARD10, growth factor signaling, mTORC1 activation, carcinogenesis, tumor immunosuppression, PD-L1, glycolysis, lung cancer, type I interferon, TBK1 phosphorylation
- MeSH terms
- A549 Cells, Mechanistic Target of Rapamycin Complex 1, Animals, Cells, Cultured, Epithelial Cells, Humans, Immune Tolerance, Immunity, Innate, Interferon Type I, Lung, Mice, Inbred C57BL, Signal Transduction, Protein Serine-Threonine Kinases, Intercellular Signaling Peptides and Proteins, Adaptor Proteins, Signal Transducing, Mice, CARD Signaling Adaptor Proteins, HEK293 Cells, Carcinogenesis
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