The IKK-related kinase TBK1 activates mTORC1 directly in response to growth factors and innate immune agonists
The IKK-related kinase TBK1 activates mTORC1 directly in response to growth factors and innate immune agonists
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DOI：
10.15252/embj.201696164
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发表时间：
2018-01-04
期刊：
影响因子：
11.4
通讯作者：
Fingar, Diane C.
中科院分区：
文献类型：
--
作者：
Bodur, Cagri;Kazyken, Dubek;Fingar, Diane C.
先天免疫激酶TBK1通过驱动I型干扰素的产生来启动对抗感染性病原体的炎症反应。TBK1还控制代谢过程，促进癌基因诱导的细胞增殖和存活。在这里，我们证明TBK1直接激活mTOR复合物1 （mTORC1）。在培养的细胞中，TBK1通过特定位点的mTOR磷酸化（在S2159上）与mTORC1结合并激活mTORC1，以响应某些生长因子受体（即egf受体，但不包括胰岛素受体）和病原体识别受体（即TLR3； TLR4），揭示TBK1在mTORC1调节中的刺激选择性作用。通过研究培养的巨噬细胞和从基因组编辑的mTOR S2159A敲入小鼠中分离的巨噬细胞，我们发现mTOR S2159磷酸化促进mTORC1信号传导、IRF3核易位和ifn - β的产生。这些数据表明TBK1和mTORC1功能之间存在直接的机制联系，以及TBK1-mTORC1轴在控制先天免疫功能中的生理意义。这些数据揭示了TBK1作为mTORC1的直接激活剂，并提示TBK1下游的mTORC1在先天免疫、肿瘤发生和慢性炎症相关疾病的控制中具有意想不到的作用。
The innate immune kinase TBK1 initiates inflammatory responses to combat infectious pathogens by driving production of type I interferons. TBK1 also controls metabolic processes and promotes oncogene-induced cell proliferation and survival. Here, we demonstrate that TBK1 activates mTOR complex 1 (mTORC1) directly. In cultured cells, TBK1 associates with and activates mTORC1 through site-specific mTOR phosphorylation (on S2159) in response to certain growth factor receptors (i.e., EGF-receptor but not insulin receptor) and pathogen recognition receptors (PRRs) (i.e., TLR3; TLR4), revealing a stimulus-selective role for TBK1 in mTORC1 regulation. By studying cultured macrophages and those isolated from genome edited mTOR S2159A knock-in mice, we show that mTOR S2159 phosphorylation promotes mTORC1 signaling, IRF3 nuclear translocation, and IFN-beta production. These data demonstrate a direct mechanistic link between TBK1 and mTORC1 function as well as physiologic significance of the TBK1-mTORC1 axis in control of innate immune function. These data unveil TBK1 as a direct mTORC1 activator and suggest unanticipated roles for mTORC1 downstream of TBK1 in control of innate immunity, tumorigenesis, and disorders linked to chronic inflammation.