TBK1 Limits mTORC1 by Promoting Phosphorylation of Raptor Ser877

Abstract

While best known for its role in the innate immune system, the TANK-binding kinase 1 (TBK1) is now known to play a role in modulating cellular growth and autophagy. One of the major ways that TBK1 accomplishes this task is by modulating the mechanistic Target of Rapamycin (mTOR), a master regulator that when activated promotes cell growth and inhibits autophagy. However, whether TBK1 promotes or inhibits mTOR activity is highly cell type and context dependent. To further understand the mechanism whereby TBK1 regulates mTOR, we tested the hypothesis that TBK1 phosphorylates a key component of the mTOR complex 1 (mTORC1), Raptor. Using kinase assays coupled with mass spectrometry, we mapped the position of the TBK1 dependent phosphorylation sites on Raptor in vitro. Among the sites identified in vitro, we found that TBK1 promotes Raptor Ser877 phosphorylation in cells both basally and in response to pathogen-associated molecules known to induce TBK1 activity. The levels of Raptor Ser877 phosphorylation were inversely correlated with the levels of mTOR activity. Expression of a mutant Raptor that could not be phosphorylated at Ser877 led to an increase in mTORC1 activity. We conclude that TBK1 limits mTORC1 activity by promoting Raptor Ser877 phosphorylation.

Exocyst protein subnetworks integrate Hippo and mTOR signaling to promote virus detection and cancer

“…YAP1 was an interacting partner of TBK1 (Figure 2A; Figure S2C). These observations were consistent with recent studies suggesting TBK1 may regulate YAP1 and the mTOR substrate S6K (Cooper et al, 2017;Wang et al, 2017;Zhang et al, 2017;Eskiocak et al, 2017;Kim et al, 2013;Antonia et al, 2019;Martin et al, 2014). Pathogen exposure formed TBK1/ mTOR complexes and suppressed TBK1/YAP1 complexes (Figures 2H and 4A).…”

Prognostic significance of autophagy-related genes within esophageal carcinoma

“…Furthermore, autophagy abolition through the ATG5/7 re-sensitized EC109/CDDP knockdown or the use of pharmacological inhibitors is greatly significant [ 36 ] not only in the esophageal, but also in gastric [ 37 ], colorectal [ 38 , 39 ], bladder [ 40 ], ovarian [ 41 ], and prostate cancers [ 42 ]. With regard to TBK1, it has been proven that TBK1 takes part in modulating cell growth and autophagy [ 43 ]. Moreover, Sarraf et al [ 44 ] also indicated that TBK1 exerted an important role in mitophagy.…”

Targeting TBK1 Attenuates LPS-Induced NLRP3 Inflammasome Activation by Regulating of mTORC1 Pathways in Trophoblasts

“…In response to LPS, TBK1 can directly activate mTORC1, but this function of TBK1 has been controversial ( 29 , 30 ). Therefore, we checked the expression of downstream target proteins of mTORC1 in the placental tissues of control, vehicle-, and amlexanox-treated LPS mice.…”