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.

PubMed Disclaimer

Conflict of interest statement

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

Cited by

STING Promotes the Progression of ADPKD by Regulating Mitochondrial Function, Inflammation, Fibrosis, and Apoptosis.
Wu J, Cheng S, Lee G, Agborbesong E, Li X, Zhou X, Li X. Wu J, et al. Biomolecules. 2024 Sep 26;14(10):1215. doi: 10.3390/biom14101215. Biomolecules. 2024. PMID: 39456148 Free PMC article.
Targeting TANK-binding kinase 1 (TBK1) in cancer.
Revach OY, Liu S, Jenkins RW. Revach OY, et al. Expert Opin Ther Targets. 2020 Nov;24(11):1065-1078. doi: 10.1080/14728222.2020.1826929. Epub 2020 Oct 5. Expert Opin Ther Targets. 2020. PMID: 32962465 Free PMC article. Review.
Chemical and Biomolecular Strategies for STING Pathway Activation in Cancer Immunotherapy.
Garland KM, Sheehy TL, Wilson JT. Garland KM, et al. Chem Rev. 2022 Mar 23;122(6):5977-6039. doi: 10.1021/acs.chemrev.1c00750. Epub 2022 Feb 2. Chem Rev. 2022. PMID: 35107989 Free PMC article. Review.
Vitamin B12 Reduces TDP-43 Toxicity by Alleviating Oxidative Stress and Mitochondrial Dysfunction.
Jeon YM, Kwon Y, Lee S, Kim S, Jo M, Lee S, Kim SR, Kim K, Kim HJ. Jeon YM, et al. Antioxidants (Basel). 2021 Dec 29;11(1):82. doi: 10.3390/antiox11010082. Antioxidants (Basel). 2021. PMID: 35052586 Free PMC article.
How the Innate Immune DNA Sensing cGAS-STING Pathway Is Involved in Autophagy.
Zheng W, Xia N, Zhang J, Chen N, Meurens F, Liu Z, Zhu J. Zheng W, et al. Int J Mol Sci. 2021 Dec 8;22(24):13232. doi: 10.3390/ijms222413232. Int J Mol Sci. 2021. PMID: 34948027 Free PMC article. Review.

See all "Cited by" articles

Publication types

Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

LinkOut - more resources

Full Text Sources
- Elsevier Science
Molecular Biology Databases
- Mouse Genome Informatics (MGI)
Research Materials
- NCI CPTC Antibody Characterization Program
Miscellaneous
- NCI CPTAC Assay Portal

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Similar articles

Cited by

Publication types

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Molecular Biology Databases

Research Materials

Miscellaneous

Abstract

Conflict of interest statement

Similar articles

Cited by

Publication types

MeSH terms

Substances

Related information

LinkOut - more resources

Full Text Sources

Molecular Biology Databases

Research Materials

Miscellaneous