@article{5ea9327f6f8b42ecbea001e77b905663,
title = "TBK1 and IKKε Act Redundantly to Mediate STING-Induced NF-κB Responses in Myeloid Cells",
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.",
keywords = "IKKε, NF-κB, STING, TBK1, cGAS, cytokines, innate immunity, protein kinases, signal transduction, type I interferons",
author = "Balka, {Katherine R.} and Cynthia Louis and Saunders, {Tahnee L.} and Smith, {Amber M.} and Calleja, {Dale J.} and D'Silva, {Damian B.} and Fiona Moghaddas and Maximilien Tailler and Lawlor, {Kate E.} and Yifan Zhan and Burns, {Christopher J.} and Wicks, {Ian P.} and Miner, {Jonathan J.} and Kile, {Benjamin T.} and Masters, {Seth L.} and {De Nardo}, Dominic",
note = "Funding Information: We acknowledge G. Belz (Walter and Eliza Hall Institute, Parkville, Australia) for HSV-1 and D. Kalvakolanu (University of Maryland, MD, USA) for J2 recombinant retroviruses. We are very grateful to C.M. De Nardo (Monash University, Australia) for carefully proofreading the manuscript. This work was supported by Australian National Health and Medical Research Council (NHMRC) Project Grants ( 1099262 to S.L.M.; 1077750 to B.T.K.; 1145788 and 1162765 to K.E.L.) and a Program Grant ( 1113577 to B.T.K. and I.P.W.). Fellowships were from the NHMRC (to S.L.M. and B.T.K.), Victorian Endowment for Science Knowledge and Innovation (to S.L.M.), HHMI-Wellcome International Research Scholarship (to S.L.M.), the Sylvia and Charles Viertel Foundation (to S.L.M.), and a Monash University FMNHS Senior Postdoctoral Fellowship (to D.D.N.). I.P.W. is further supported by the Reid Charitable Trusts , a NHMRC Clinical Practitioner Fellowship (grant 1023407 ), Development Grant ( 1055374 ), IRIISS (grant 9000220 ), and a Victorian State Government Operational Infrastructure Support Grant . Funding Information: We acknowledge G. Belz (Walter and Eliza Hall Institute, Parkville, Australia) for HSV-1 and D. Kalvakolanu (University of Maryland, MD, USA) for J2 recombinant retroviruses. We are very grateful to C.M. De Nardo (Monash University, Australia) for carefully proofreading the manuscript. This work was supported by Australian National Health and Medical Research Council (NHMRC) Project Grants (1099262 to S.L.M.; 1077750 to B.T.K.; 1145788 and 1162765 to K.E.L.) and a Program Grant (1113577 to B.T.K. and I.P.W.). Fellowships were from the NHMRC (to S.L.M. and B.T.K.), Victorian Endowment for Science Knowledge and Innovation (to S.L.M.), HHMI-Wellcome International Research Scholarship (to S.L.M.), the Sylvia and Charles Viertel Foundation (to S.L.M.), and a Monash University FMNHS Senior Postdoctoral Fellowship (to D.D.N.). I.P.W. is further supported by the Reid Charitable Trusts, a NHMRC Clinical Practitioner Fellowship (grant 1023407), Development Grant (1055374), IRIISS (grant 9000220), and a Victorian State Government Operational Infrastructure Support Grant. Conceptualization, D.D.N.; Methodology, D.D.N. K.R.B. C.L. A.M.S. and J.J.M.; Validation, D.D.N. and K.R.B.; Formal Analysis, D.D.N. K.R.B. T.L.S. A.M.S. and J.J.M.; Investigation, K.R.B. D.D.N. C.L. T.L.S. D.J.C. D.B.D.S. F.M. M.T. K.E.L. and Y.Z.; Resources, C.J.B. I.P.W. B.T.K. and S.L.M.; Writing ? Original Draft, K.R.B. and D.D.N.; Writing ? Review & Editing, K.R.B. and D.D.N. with input from all authors; Funding Acquisition, B.T.K. and S.L.M.; Supervision, B.T.K. S.L.M. and D.D.N. S.L.M. receives funding from GlaxoSmithKline. Publisher Copyright: {\textcopyright} 2020 The Author(s)",
year = "2020",
month = apr,
day = "7",
doi = "10.1016/j.celrep.2020.03.056",
language = "English",
volume = "31",
journal = "Cell Reports",
issn = "2211-1247",
number = "1",
}