TBK1 and IKKε Act Redundantly to Mediate STING-Induced NF-κB Responses in Myeloid Cells

Katherine R. Balka, Cynthia Louis, Tahnee L. Saunders, Amber M. Smith, Dale J. Calleja, Damian B. D'Silva, Fiona Moghaddas, Maximilien Tailler, Kate E. Lawlor, Yifan Zhan, Christopher J. Burns, Ian P. Wicks, Jonathan J. Miner, Benjamin T. Kile, Seth L. Masters, Dominic De Nardo

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4 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number107492
Number of pages22
JournalCell Reports
Volume31
Issue number1
DOIs
Publication statusPublished - 7 Apr 2020

Keywords

  • cGAS
  • cytokines
  • IKKε
  • innate immunity
  • NF-κB
  • protein kinases
  • signal transduction
  • STING
  • TBK1
  • type I interferons

Cite this

Balka, 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 IKKε Act Redundantly to Mediate STING-Induced NF-κB Responses in Myeloid Cells. Cell Reports, 31(1), [107492]. https://doi.org/10.1016/j.celrep.2020.03.056