TBKBP1 and TBK1 form a growth factor signalling axis mediating immunosuppression and tumourigenesis

• Published in: Nature cell biology Vol. 21; no. 12; pp. 1604 - 1614
• Main Authors: Zhu, Lele, Li, Yanchuan, Xie, Xiaoping, Zhou, Xiaofei, Gu, Meidi, Jie, Zuliang, Ko, Chun-Jung, Gao, Tianxiao, Hernandez, Blanca E., Cheng, Xuhong, Sun, Shao-Cong
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.12.2019; Nature Publishing Group
• Subjects: 38/89; 631/67; 631/67/580; 631/80/86/2368; 64/60; 82/29; 96/106; 96/31; 96/95; A549 Cells; Activation; Adaptor Proteins, Signal Transducing - genetics; Analysis; Animals; Biological response modifiers; Biomedical and Life Sciences; Cancer Research; Carcinogenesis - genetics; CARD Signaling Adaptor Proteins - genetics; Cell Biology; Cells, Cultured; Clonal deletion; Developmental Biology; Epithelial cells; Epithelial Cells - pathology; Glycolysis; Growth factors; HEK293 Cells; Humans; Immune Tolerance - genetics; Immunity, Innate - genetics; Immunosuppression; Immunotherapy; Intercellular Signaling Peptides and Proteins - genetics; Interferon; Interferon Type I - genetics; Kinases; Life Sciences; Lung - pathology; Lung cancer; Mechanistic Target of Rapamycin Complex 1 - genetics; Mice; Mice, Inbred C57BL; Microorganisms; PD-L1 protein; Protein binding; Protein kinase C; Protein kinases; Protein Serine-Threonine Kinases - genetics; Proteins; Signal Transduction - genetics; Signaling; Stem Cells; Stimuli; Tumorigenesis; Tumors
• ISSN: 1465-7392; 1476-4679; 1476-4679
• DOI: 10.1038/s41556-019-0429-8

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. Zhu et al. show that, in response to growth factors, TBKBP1 recruits TBK1 to promote its activation by PKCθ, thereby facilitating mTORC1 activation, tumour-mediated immunosuppression and tumourigenesis.