TBK1 and IKK epsilon Act Redundantly to Mediate STING-Induced NF-kappa B Responses in Myeloid Cells
AuthorBalka, KR; Louis, C; Saunders, TL; Smith, AM; Calleja, DJ; D'Silva, DB; Moghaddas, F; Tailler, M; Lawlor, KE; Zhan, Y; ...
Source TitleCell Reports
University of Melbourne Author/sTailler, Maximilien; Lawlor, Kathryn; Zhan, Yifan; Wicks, Ian; Masters, Seth; Burns, Christopher; de Nardo, Dominic; Louis, Cynthia
AffiliationMedical Biology (W.E.H.I.)
Medicine and Radiology
School of Chemistry
Document TypeJournal Article
CitationsBalka, K. R., Louis, C., Saunders, T. L., Smith, A. M., Calleja, D. J., D'Silva, D. B., Moghaddas, F., Tailler, M., Lawlor, K. E., Zhan, Y., Burns, C. J., Wicks, I. P., Miner, J. J., Kile, B. T., Masters, S. L. & De Nardo, D. (2020). TBK1 and IKK epsilon Act Redundantly to Mediate STING-Induced NF-kappa B Responses in Myeloid Cells. CELL REPORTS, 31 (1), https://doi.org/10.1016/j.celrep.2020.03.056.
Access StatusOpen Access
Stimulator of Interferon Genes (STING) is a critical component of host innate immune defense but can contribute to chronic autoimmune or autoinflammatory disease. Once activated, the cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) (cGAMP) synthase (cGAS)-STING pathway induces both type I interferon (IFN) expression and nuclear factor-κB (NF-κB)-mediated cytokine production. Currently, these two signaling arms are thought to be mediated by a single upstream kinase, TANK-binding kinase 1 (TBK1). Here, using genetic and pharmacological approaches, we show that TBK1 alone is dispensable for STING-induced NF-κB responses in human and mouse immune cells, as well as in vivo. We further demonstrate that TBK1 acts redundantly with IκB kinase ε (IKKε) to drive NF-κB upon STING activation. Interestingly, we show that activation of IFN regulatory factor 3 (IRF3) is highly dependent on TBK1 kinase activity, whereas NF-κB is significantly less sensitive to TBK1/IKKε kinase inhibition. Our work redefines signaling events downstream of cGAS-STING. Our findings further suggest that cGAS-STING will need to be targeted directly to effectively ameliorate the inflammation underpinning disorders associated with STING hyperactivity.
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