| First Author | Bodur C | Year | 2018 |
| Journal | EMBO J | Volume | 37 |
| Issue | 1 | Pages | 19-38 |
| PubMed ID | 29150432 | Mgi Jnum | J:257513 |
| Mgi Id | MGI:6118030 | Doi | 10.15252/embj.201696164 |
| Citation | Bodur C, et al. (2018) The IKK-related kinase TBK1 activates mTORC1 directly in response to growth factors and innate immune agonists. EMBO J 37(1):19-38 |
| abstractText | 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. |
