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.
journal_name
Cell Repjournal_title
Cell reportsauthors
Balka KR,Louis C,Saunders TL,Smith AM,Calleja DJ,D'Silva DB,Moghaddas F,Tailler M,Lawlor KE,Zhan Y,Burns CJ,Wicks IP,Miner JJ,Kile BT,Masters SL,De Nardo Ddoi
10.1016/j.celrep.2020.03.056subject
Has Abstractpub_date
2020-04-07 00:00:00pages
107492issue
1issn
2211-1247pii
S2211-1247(20)30370-3journal_volume
31pub_type
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