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

Abstract

The kinase TBK1 responds to microbial stimuli and mediates type I interferon (IFN-I) induction. We show that TBK1 is also a central mediator of growth factor signaling; this function relies on a specific adaptor, TBK-binding protein 1 (TBKBP1). TBKBP1 recruits TBK1 to PKCθ via a scaffold protein, Card10, which allows PKCθ to phosphorylate TBK1 at serine-716, a crucial step for TBK1 activation by growth factors but not by innate immune stimuli. While the TBK1/TBKBP1 signaling axis is dispensable for IFN-I induction, it mediates mTORC1 activation and oncogenesis. Lung epithelial cell-conditional deletion of either TBK1 or TBKBP1 inhibits tumorigenesis in a mouse model of lung cancer. In addition to promoting tumor growth, the TBK1/TBKBP1 axis facilitates tumor-mediated immunosuppression by a mechanism involving induction of the checkpoint molecule PD-L1 and stimulation of glycolysis. These findings suggest a PKCθ-TBKBP1-TBK1 growth factor signaling axis mediating both tumor growth and immunosuppression.