TBK1 and IKKepsilon act redundantly to mediate STING-I-induced NF-kappaB responses in myeloid cells

Balka, KR; Louis, C; Saunders, TL; Smith, AM; Calleja, DJ; D&#39;Silva, DB; Moghaddas, F; Tailler, M; Lawlor, KE; Zhan, Y; Burns, CJ; Wicks, IP; Miner, JJ; Kile, BT; Masters, SL; De Nardo, D

Author(s): 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, D;
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
Research Division(s): Inflammation; Ubiquitin Signalling; Immunology
PubMed ID: 32268090
Publisher's Version: https://doi.org/10.1016/j.celrep.2020.03.056
Open Access at Publisher's Site: https://doi.org10.1016/j.celrep.2020.03.056
NHMRC Grants: NHMRC/1077750, NHMRC/1113577, NHMRC/1145788, NHMRC/1099262, NHMRC/1023407,
Terms of Use/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