Cell Reports (Apr 2020)

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

Journal volume & issue
Vol. 31, no. 1

Abstract

Read online

Summary: 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. : Activation of NF-κB via STING is considered to be exclusively dependent on TBK1. Balka et al. now show that, although TBK1 and its kinase activity are critical for IRF3 activation and type I IFNs, it is dispensable for NF-κB. Instead, TBK1 and IKKε act redundantly to mediate STING-induced NF-κB responses. Keywords: STING, cGAS, innate immunity, NF-κB, TBK1, IKKε, signal transduction, type I interferons, cytokines, protein kinases