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Nat Commun. 2018 Aug 29;9(1):3506. doi: 10.1038/s41467-018-05861-7.

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

Author information

1
Department of Biomedicine, Aarhus Research Center for Innate Immunology, Aarhus University, Bartholin Alle 6, 8000, Aarhus, Denmark. olagnier@biomed.au.dk.
2
Department of Biomedicine, Aarhus Research Center for Innate Immunology, Aarhus University, Bartholin Alle 6, 8000, Aarhus, Denmark.
3
Department of Chemistry, Aarhus University, Langelandsgade 140, 8000, Aarhus, Denmark.
4
Fox Chase Cancer Center, 333 Cottman Avenue, Philidelphia, PA, 19111-2497, USA.
5
Department of Food Science, Aarhus University, Kirstinebjergvej 10, 5792, Aarslev, Denmark.
6
Lady Davis Institute-Jewish General Hospital, McGill University, Division of Experimental Medicine, 3755 Côte Ste-Catherine Road, Montreal, QC, H3T 1E2, Canada.
7
BGI-Shenzhen, Beishan Industrial Zone, Yantian District, Shenzhen, 518083, China.
8
Translational Autoinflammatory Diseases Studies, NIAID, NIH, 10 Center Drive, Bethesda, MD, 20892, USA.
9
Program in Innate Immunity, Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA, 01605, USA.
10
School of biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College, College Green, Dublin 2, D02 PN40, Ireland, UK.
11
Department of Molecular Biology and Genetics, Aarhus University, C.F. Moellers Allé 3, 8000, Aarhus, Denmark.
12
Department of Biomedicine, Aarhus Research Center for Innate Immunology, Aarhus University, Bartholin Alle 6, 8000, Aarhus, Denmark. holm@biomed.au.dk.

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.

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