The IKK-related kinase TBK1 activates mTORC1 directly in response to growth factors and innate immune agonists.

Abstract

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-β 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.

• Authors: Cagri Bodur, Dubek Kazyken, Kezhen Huang, Bilgen Ekim Ustunel, Kate A Siroky, Aaron Seth Tooley, Ian E Gonzalez, Daniel H Foley, Hugo A Acosta-Jaquez, Tammy M Barnes, Gabrielle K Steinl, Kae-Won Cho, Carey N Lumeng, Steven M Riddle, Martin G Myers Jr, Diane C Fingar
• Journal: The EMBO journal (EMBO J) Vol. 37 Issue 1 Pg. 19-38 (01 04 2018) ISSN: 1460-2075 [Electronic] England
• PMID: 29150432 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2017 The Authors.

Chemical References

• IRF3 protein, human
• Intercellular Signaling Peptides and Proteins
• Interferon Regulatory Factor-3
• MTOR protein, human
• Mechanistic Target of Rapamycin Complex 1
• Protein Serine-Threonine Kinases
• TBK1 protein, human
• TOR Serine-Threonine Kinases

Topics

• Animals
• Cell Nucleus (metabolism)
• Cells, Cultured
• Cytosol (metabolism)
• Humans
• Immunity, Innate (drug effects)
• Intercellular Signaling Peptides and Proteins (pharmacology)
• Interferon Regulatory Factor-3 (genetics, metabolism)
• Macrophages (drug effects, immunology, metabolism)
• Mechanistic Target of Rapamycin Complex 1 (genetics, metabolism)
• Mice
• Phosphorylation (drug effects)
• Protein Serine-Threonine Kinases (genetics, metabolism)
• Protein Transport
• Signal Transduction (drug effects)
• TOR Serine-Threonine Kinases (genetics, metabolism)