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Sci Rep. 2019 Sep 17;9(1):13470. doi: 10.1038/s41598-019-49707-8.

TBK1 Limits mTORC1 by Promoting Phosphorylation of Raptor Ser877.

Author information

1
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
2
The Helen Diller Family Comprehensive Cancer Center, The University of California San Francisco, San Francisco, California, USA.
3
UNC Proteomics Core Facility, Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, USA.
4
Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, USA.
5
Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, USA.
6
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. albert_baldwin@med.unc.edu.
7
Division of Pulmonary Diseases and Critical Care Medicine, Department of Medicine, University of North Carolina, Chapel Hill, NC, 27599, USA. robhagan@email.unc.edu.
8
Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA. robhagan@email.unc.edu.

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.

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