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.

A post-transcriptional program of chemoresistance by AU-rich elements and TTP in quiescent leukemic cells

“…This indicates that the mTOR pathway shows differences at different levels in SS and AraCS cells. This is likely due to feedback on mTOR from downstream S6K and other kinases, as observed in other systems [26,[36][37][38][39][40][41], while 4EBP is also known to be regulated by other kinases, independent of mTOR [42][43][44][45]. Thus, while the eIF2 pathway is strongly inhibited in SS and AraCS cells at similar levels ( Fig.…”

“…2d), mTOR phosphorylation was not coordinately altered (Additional file 1: Figure S1I), indicating that the mTOR pathway shows differences at different levels in SS and AraCS cells. This is likely due to feedback regulation from S6K and other downstream kinases that can affect mTOR, as observed in other systems [26,[36][37][38][39][40][41], while 4EBP is also known to be regulated by other kinases, independent of mTOR [42][43][44][45].…”

High Content Screening and Proteomic Analysis Identify a Kinase Inhibitor that rescues pathological phenotypes in a Patient-Derived Model of Parkinson’s Disease

“…Yet four other PDK1 inhibitors that were included in the Selleck library did not emerge as hits during the screening campaign. TBK1 was recently suggested as a new player linking autophagy and neuroinflammation in ALS [85] and has been shown to activate mTOR directly in response to growth factors [87]. In agreement, we demonstrated an acute effect of BX795 in mTOR, RPS6 and PRAS40 phosphorylation in p.A53T-expressing neuroblastoma cells.…”

IKBKE inhibits TSC1 to activate the mTOR/S6K pathway for oncogenic transformation

“…One plausible explanation could be that IKKε deficiency leads to downregulation of mTORC activity due to diminished AKT phosphoactivation (Xie et al, 2011;Huang and Fingar, 2014). Moreover, it is also possible that IKKε may directly phosphorylate the mTORC complex, similarly to the IKK-related kinase TBK1 upon growth factor or innate immunity agonist stimulation in immune cells (Bodur et al, 2018). However, direct interference by IKKε on mTORC or its upstream elements like AKT can be ruled out in this case, since mTOR phosphorylation is not affected in SW480 cells.…”