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

Cell Rep. 2020 Apr 7;31(1):107492. doi: 10.1016/j.celrep.2020.03.056.

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.

Keywords: IKKε; NF-κB; STING; TBK1; cGAS; cytokines; innate immunity; protein kinases; signal transduction; type I interferons.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Female
  • HEK293 Cells
  • Humans
  • I-kappa B Kinase / metabolism*
  • I-kappa B Kinase / physiology
  • Immunity, Innate
  • Interferon Regulatory Factor-3 / metabolism
  • Interferon-beta / metabolism
  • Male
  • Membrane Proteins / metabolism
  • Membrane Proteins / physiology
  • Mice
  • Mice, Inbred C57BL
  • Myeloid Cells / metabolism
  • NF-kappa B / metabolism
  • Nucleotides, Cyclic / metabolism
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / metabolism*
  • Protein-Serine-Threonine Kinases / physiology
  • Signal Transduction / immunology

Substances

  • Interferon Regulatory Factor-3
  • Membrane Proteins
  • NF-kappa B
  • Nucleotides, Cyclic
  • STING1 protein, human
  • cyclic guanosine monophosphate-adenosine monophosphate
  • Interferon-beta
  • Protein-Serine-Threonine Kinases
  • TBK1 protein, human
  • I-kappa B Kinase
  • IKBKE protein, human