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Nrf2 negatively regulates STING indicating a link between antiviral sensing and metabolic reprogramming

Author

Listed:
  • David Olagnier

    (Aarhus Research Center for Innate Immunology, Aarhus University)

  • Aske M. Brandtoft

    (Aarhus Research Center for Innate Immunology, Aarhus University)

  • Camilla Gunderstofte

    (Aarhus Research Center for Innate Immunology, Aarhus University)

  • Nikolaj L. Villadsen

    (Aarhus University)

  • Christian Krapp

    (Aarhus Research Center for Innate Immunology, Aarhus University)

  • Anne L. Thielke

    (Aarhus Research Center for Innate Immunology, Aarhus University)

  • Anders Laustsen

    (Aarhus Research Center for Innate Immunology, Aarhus University)

  • Suraj Peri

    (Fox Chase Cancer Center)

  • Anne Louise Hansen

    (Aarhus Research Center for Innate Immunology, Aarhus University)

  • Lene Bonefeld

    (Aarhus Research Center for Innate Immunology, Aarhus University)

  • Jacob Thyrsted

    (Aarhus Research Center for Innate Immunology, Aarhus University)

  • Victor Bruun

    (Aarhus Research Center for Innate Immunology, Aarhus University)

  • Marie B. Iversen

    (Aarhus Research Center for Innate Immunology, Aarhus University)

  • Lin Lin

    (Aarhus Research Center for Innate Immunology, Aarhus University)

  • Virginia M. Artegoitia

    (Aarhus University)

  • Chenhe Su

    (McGill University, Division of Experimental Medicine)

  • Long Yang

    (McGill University, Division of Experimental Medicine)

  • Rongtuan Lin

    (McGill University, Division of Experimental Medicine)

  • Siddharth Balachandran

    (Fox Chase Cancer Center)

  • Yonglun Luo

    (Aarhus Research Center for Innate Immunology, Aarhus University
    BGI-Shenzhen, Beishan Industrial Zone, Yantian District)

  • Mette Nyegaard

    (Aarhus Research Center for Innate Immunology, Aarhus University)

  • Bernadette Marrero

    (NIAID)

  • Raphaela Goldbach-Mansky

    (NIAID)

  • Mona Motwani

    (University of Massachusetts Medical School)

  • Dylan G. Ryan

    (Trinity Biomedical Sciences Institute, Trinity College, College Green)

  • Katherine A. Fitzgerald

    (University of Massachusetts Medical School)

  • Luke A. O’Neill

    (Trinity Biomedical Sciences Institute, Trinity College, College Green)

  • Anne K. Hollensen

    (Aarhus University)

  • Christian K. Damgaard

    (Aarhus University)

  • Frank v. Paoli

    (Aarhus Research Center for Innate Immunology, Aarhus University)

  • Hanne C. Bertram

    (Aarhus University)

  • Martin R. Jakobsen

    (Aarhus Research Center for Innate Immunology, Aarhus University)

  • Thomas B. Poulsen

    (Aarhus University)

  • Christian K. Holm

    (Aarhus Research Center for Innate Immunology, Aarhus University)

Abstract

The transcription factor Nrf2 is a critical regulator of inflammatory responses. If and how Nrf2 also affects cytosolic nucleic acid sensing is currently unknown. Here we identify Nrf2 as an important negative regulator of STING and suggest a link between metabolic reprogramming and antiviral cytosolic DNA sensing in human cells. Here, Nrf2 activation decreases STING expression and responsiveness to STING agonists while increasing susceptibility to infection with DNA viruses. Mechanistically, Nrf2 regulates STING expression by decreasing STING mRNA stability. Repression of STING by Nrf2 occurs in metabolically reprogrammed cells following TLR4/7 engagement, and is inducible by a cell-permeable derivative of the TCA-cycle-derived metabolite itaconate (4-octyl-itaconate, 4-OI). Additionally, engagement of this pathway by 4-OI or the Nrf2 inducer sulforaphane is sufficient to repress STING expression and type I IFN production in cells from patients with STING-dependent interferonopathies. We propose Nrf2 inducers as a future treatment option in STING-dependent inflammatory diseases.

Suggested Citation

  • David Olagnier & Aske M. Brandtoft & Camilla Gunderstofte & Nikolaj L. Villadsen & Christian Krapp & Anne L. Thielke & Anders Laustsen & Suraj Peri & Anne Louise Hansen & Lene Bonefeld & Jacob Thyrste, 2018. "Nrf2 negatively regulates STING indicating a link between antiviral sensing and metabolic reprogramming," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-05861-7
    DOI: 10.1038/s41467-018-05861-7
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    Cited by:

    1. Xudong Wang & Siyu Su & Yuqing Zhu & Xiaolong Cheng & Chen Cheng & Leilei Chen & Anhua Lei & Li Zhang & Yuyan Xu & Dan Ye & Yi Zhang & Wei Li & Jin Zhang, 2023. "Metabolic Reprogramming via ACOD1 depletion enhances function of human induced pluripotent stem cell-derived CAR-macrophages in solid tumors," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    2. Naziia Kurmasheva & Aida Said & Boaz Wong & Priscilla Kinderman & Xiaoying Han & Anna H. F. Rahimic & Alena Kress & Madalina E. Carter-Timofte & Emilia Holm & Demi Horst & Christoph F. Kollmann & Zhen, 2024. "Octyl itaconate enhances VSVΔ51 oncolytic virotherapy by multitarget inhibition of antiviral and inflammatory pathways," Nature Communications, Nature, vol. 15(1), pages 1-28, December.

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