TY - JOUR
T1 - TBKBP1 and TBK1 form a growth factor signalling axis mediating immunosuppression and tumourigenesis
AU - Zhu, Lele
AU - Li, Yanchuan
AU - Xie, Xiaoping
AU - Zhou, Xiaofei
AU - Gu, Meidi
AU - Jie, Zuliang
AU - Ko, Chun Jung
AU - Gao, Tianxiao
AU - Hernandez, Blanca E.
AU - Cheng, Xuhong
AU - Sun, Shao Cong
N1 - Funding Information:
We thank F. Zhu, C. Wang and X. Lin for plasmid DNAs; S. Akira for Tank knockout mice and F. J. DeMayo for the Ccspcre mice; the personnel from the flow cytometry, DNA analysis and animal facilities at The MD Anderson Cancer Center and the Mass Spectrometry Proteomics Core at Baylor College of Medicine for technical assistance. This study was supported by a National Institutes of Health grant (AI057555) and partially supported by a seed fund from the Center for Inflammation and Cancer at the MD Anderson Cancer Center. T.G. was a visiting student supported by a scholarship from the China Scholarship Council (grant number 201906380080). The MD Anderson core facilities are supported by a NIH/NCI Cancer Center Support Grant (CCSG; P30CA016672), and the Baylor College of Medicine Mass Spectrometry Proteomics Core is supported by a CPRIT Core Facility Award (RP170005) and a P30 Cancer Center Support Grant (NCI-CA125123).
Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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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U2 - 10.1038/s41556-019-0429-8
DO - 10.1038/s41556-019-0429-8
M3 - Article
C2 - 31792381
AN - SCOPUS:85076049798
VL - 21
SP - 1604
EP - 1614
JO - Nature
JF - Nature
SN - 0028-0836
IS - 12
ER -