TBK1 and IKKε Act Redundantly to Mediate STING-Induced NF-κB Responses in Myeloid Cells

doi:10.1016/j.celrep.2020.03.056

. 2020 Apr 7;31(1):107492.

doi: 10.1016/j.celrep.2020.03.056.

TBK1 and IKKε Act Redundantly to Mediate STING-Induced NF-κB Responses in Myeloid Cells

Katherine R Balka¹, Cynthia Louis², Tahnee L Saunders³, Amber M Smith⁴, Dale J Calleja², Damian B D'Silva², Fiona Moghaddas², Maximilien Tailler³, Kate E Lawlor⁵, Yifan Zhan⁶, Christopher J Burns⁷, Ian P Wicks⁸, Jonathan J Miner⁴, Benjamin T Kile⁹, Seth L Masters², Dominic De Nardo¹⁰

Affiliations

¹ Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia; Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia.
² Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia.
³ Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia.
⁴ Departments of Medicine, Molecular Microbiology, and Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
⁵ Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Department of Molecular and Translational Science, Monash University, Clayton, VIC 3168, Australia.
⁶ Immunology Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia.
⁷ Chemical Biology Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia.
⁸ Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia; Rheumatology Unit, Royal Melbourne Hospital, Parkville, VIC 3050, Australia.
⁹ Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; Health and Medical Sciences Faculty Office, University of Adelaide, Adelaide, SA 5005, Australia.
¹⁰ Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia; Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia. Electronic address: dominic.denardo@monash.edu.

PMID: 32268090
DOI: 10.1016/j.celrep.2020.03.056

Free article

TBK1 and IKKε Act Redundantly to Mediate STING-Induced NF-κB Responses in Myeloid Cells

Katherine R Balka et al. Cell Rep. 2020.

Free article

. 2020 Apr 7;31(1):107492.

doi: 10.1016/j.celrep.2020.03.056.

Authors

Affiliations

¹ Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia; Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia.
² Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia.
³ Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia.
⁴ Departments of Medicine, Molecular Microbiology, and Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
⁵ Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Department of Molecular and Translational Science, Monash University, Clayton, VIC 3168, Australia.
⁶ Immunology Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia.
⁷ Chemical Biology Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia.
⁸ Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia; Rheumatology Unit, Royal Melbourne Hospital, Parkville, VIC 3050, Australia.
⁹ Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; Health and Medical Sciences Faculty Office, University of Adelaide, Adelaide, SA 5005, Australia.
¹⁰ Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia; Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia. Electronic address: dominic.denardo@monash.edu.

PMID: 32268090
DOI: 10.1016/j.celrep.2020.03.056

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.

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Conflict of interest statement

Declaration of Interests S.L.M. receives funding from GlaxoSmithKline.

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TBK1 and IKKε Act Redundantly to Mediate STING-Induced NF-κB Responses in Myeloid Cells

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TBK1 and IKKε Act Redundantly to Mediate STING-Induced NF-κB Responses in Myeloid Cells

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