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The IKK‐related kinase TBK1 activates mTORC1 directly in response to growth factors and innate immune agonists
Author(s) -
Bodur Cagri,
Kazyken Dubek,
Huang Kezhen,
Ekim Ustunel Bilgen,
Siroky Kate A,
Tooley Aaron Seth,
Gonzalez Ian E,
Foley Daniel H,
AcostaJaquez Hugo A,
Barnes Tammy M,
Steinl Gabrielle K,
Cho KaeWon,
Lumeng Carey N,
Riddle Steven M,
Myers Martin G,
Fingar Diane C
Publication year - 2017
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201696164
Subject(s) - mtorc1 , biology , tank binding kinase 1 , innate immune system , microbiology and biotechnology , pi3k/akt/mtor pathway , iκb kinase , tlr3 , signal transduction , cancer research , immune system , immunology , toll like receptor , nf κb , protein kinase b , map kinase kinase kinase
The innate immune kinase TBK 1 initiates inflammatory responses to combat infectious pathogens by driving production of type I interferons. TBK 1 also controls metabolic processes and promotes oncogene‐induced cell proliferation and survival. Here, we demonstrate that TBK 1 activates mTOR complex 1 ( mTORC 1) directly. In cultured cells, TBK 1 associates with and activates mTORC 1 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 ( PRR s) (i.e., TLR 3; TLR 4), revealing a stimulus‐selective role for TBK 1 in mTORC 1 regulation. By studying cultured macrophages and those isolated from genome edited mTOR S2159A knock‐in mice, we show that mTOR S2159 phosphorylation promotes mTORC 1 signaling, IRF 3 nuclear translocation, and IFN ‐β production. These data demonstrate a direct mechanistic link between TBK 1 and mTORC 1 function as well as physiologic significance of the TBK 1‐ mTORC 1 axis in control of innate immune function. These data unveil TBK 1 as a direct mTORC 1 activator and suggest unanticipated roles for mTORC 1 downstream of TBK 1 in control of innate immunity, tumorigenesis, and disorders linked to chronic inflammation.