TBK1 and IKKepsilon act redundantly to mediate STING-I-induced NF-kappaB responses in myeloid cells
Details
Publication Year 2020-04-07, Volume 31, Issue #1, Page 107492
Journal Title
Cell Reports
Publication Type
Journal Article
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-kappaB (NF-kappaB)-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-kappaB responses in human and mouse immune cells, as well as in vivo. We further demonstrate that TBK1 acts redundantly with IkappaB kinase epsilon (IKKepsilon) to drive NF-kappaB upon STING activation. Interestingly, we show that activation of IFN regulatory factor 3 (IRF3) is highly dependent on TBK1 kinase activity, whereas NF-kappaB is significantly less sensitive to TBK1/IKKepsilon 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.
Publisher
Cell Press
WEHI Research Division(s)
Inflammation; Ubiquitin Signalling; Immunology
PubMed ID
32268090
Open Access at Publisher's Site
https://doi.org10.1016/j.celrep.2020.03.056
Rights Notice
Refer to copyright notice on published article.


Creation Date: 2020-05-04 09:07:12
Last Modified: 2020-05-04 10:18:36
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