TBKBP1 and TBK1 form a growth factor signalling axis mediating immunosuppression and tumourigenesis.,Nature Cell Biology

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TBKBP1 and TBK1 form a growth factor signalling axis mediating immunosuppression and tumourigenesis.
Nature Cell Biology ( IF 17.3 ) Pub Date : 2019-12-02 , DOI: 10.1038/s41556-019-0429-8
Lele Zhu ₁ , Yanchuan Li ₁ , Xiaoping Xie ₁ , Xiaofei Zhou ₁ , Meidi Gu ₁ , Zuliang Jie ₁ , Chun-Jung Ko ₁ , Tianxiao Gao ₁ , Blanca E Hernandez ₁ , Xuhong Cheng ₁ , Shao-Cong Sun _{1,

2}

Affiliation

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.

中文翻译：

TBKBP1 和 TBK1 形成一个生长因子信号轴，介导免疫抑制和肿瘤发生。

TANK 结合激酶 1 (TBK1) 响应微生物刺激并介导 I 型干扰素 (IFN) 的诱导。在这里，我们表明 TBK1 也是生长因子信号传导的中心介质。TBK1 的这一功能依赖于特定的适配器-TBK 结合蛋白 1 (TBKBP1)。TBKBP1 通过支架蛋白 CARD10 将 TBK1 招募到蛋白激酶 C-theta (PKCθ)。这使 PKCθ 能够在 Ser 716 处磷酸化 TBK1，这是通过生长因子而非先天免疫刺激激活 TBK1 的关键步骤。虽然 TBK1-TBKBP1 信号轴不是诱导 I 型 IFN 所必需的，但它介导 mTORC1 激活和肿瘤发生。肺上皮细胞中 TBK1 或 TBKBP1 的条件性缺失可抑制肺癌小鼠模型中的肿瘤发生。除了促进肿瘤生长，TBK1-TBKBP1 轴通过诱导检查点分子 PD-L1 和刺激糖酵解的机制促进肿瘤介导的免疫抑制。这些发现表明 PKCθ-TBKBP1-TBK1 生长因子信号轴介导肿瘤生长和免疫抑制。

更新日期：2019-12-02

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