Poster Presentation Lorne Infection and Immunity 2020

Mechanisms governing STING-induced NF-κB responses (#125)

Katherine R Balka 1 , Cynthia Louis 2 , Tahnee L Saunders 1 , Amber M Smith 3 , Dale J Calleja 2 , Damian B D’Silva 2 , Fiona Moghaddas 2 , Maximilien Tailler 1 , Kate E Lawlor 4 , Yifan Zhan 5 , Christopher J Burns 5 , Ian P Wicks 2 , Jonathan J Miner 3 , Benjamin T Kile 1 , Seth L Masters 2 , Dominic De Nardo 1
  1. Monash Biomedical Discovery Institute, Monash University, Clayton, VICTORIA, Australia
  2. Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, , Parkville, Victoria, Australia
  3. Washington University School of Medicine, St. Louis, MO, USA
  4. Hudson Institute of Medical Research, Clayton, Victoria, Australia
  5. The Walter and Eliza Hall Institute of Medical Research,, Parkville, Victoria, Australia

STING is a critical component of host innate immune defense to viruses, but can also contribute to chronic autoimmune or autoinflammatory disease. Once activated, the cGAS-STING pathway induces both type I IFN expression and NF-kB-mediated cytokine production. Currently these two signaling arms are thought to be mediated via the upstream kinase, TANK-binding kinase 1 (TBK1). Recent work highlights that NF-kB, rather than type I IFN, may play a major role in the pathology derived from STING activation in vivo. Whilst the mechanism to induce type I IFNs downstream of STING are well understood, how STING elicits NF-kB activation remains poorly described.  Here, using pharmacological and genetic approaches we show that TBK1 alone is not required for STING-induced NF-kB-dependent cytokine production in human and mouse immune cells, as well as in vivo. Our results redefine the signaling events downstream of cGAS-STING, providing significant insight into the potential limitations of TBK1 inhibition in the clinic. Furthermore, they suggest that cGAS-STING will need to be targeted directly to effectively ameliorate the inflammation underpinning chronic immune disorders associated with STING hyperactivity.