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

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  • David Olagnier
  • Aske M Brandtoft
  • Camilla Gunderstofte, Department of Biomedicine, Aarhus Research Center for Innate Immunology, Aarhus University, Bartholin Alle 6, 8000, Aarhus, Denmark., Nikolaj L Villadsen,
  • Christian Krapp
  • Anne L Thielke
  • Anders Laustsen
  • Suraj Peri, Fox Chase Cancer Center, 333 Cottman Avenue, Philidelphia, PA, 19111-2497, USA.,
  • Anne Louise Hansen
  • Lene Bonefeld, Jacob Thyrsted, Department of Biomedicine, Aarhus Research Center for Innate Immunology, Aarhus University, Bartholin Alle 6, 8000, Aarhus, Denmark.,
  • Victor Bruun
  • Marie B Iversen
  • Lin Lin,
  • Virginia M Artegoitia
  • Chenhe Su, Lady Davis Institute-Jewish General Hospital, McGill University, Division of Experimental Medicine, 3755 Côte Ste-Catherine Road, Montreal, QC, H3T 1E2, Canada., Long Yang, Lady Davis Institute-Jewish General Hospital, McGill University, Division of Experimental Medicine, 3755 Côte Ste-Catherine Road, Montreal, QC, H3T 1E2, Canada., Rongtuan Lin, Lady Davis Institute-Jewish General Hospital, McGill University, Division of Experimental Medicine, 3755 Côte Ste-Catherine Road, Montreal, QC, H3T 1E2, Canada., Siddharth Balachandran, Fox Chase Cancer Center, 333 Cottman Avenue, Philidelphia, PA, 19111-2497, USA.,
  • Yonglun Luo
  • Mette Nyegaard
  • Bernadette Marrero, Translational Autoinflammatory Diseases Studies, NIAID, NIH, 10 Center Drive, Bethesda, MD, 20892, USA., Raphaela Goldbach-Mansky, Translational Autoinflammatory Diseases Studies, NIAID, NIH, 10 Center Drive, Bethesda, MD, 20892, USA., Mona Motwani, 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., Dylan G Ryan, School of biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College, College Green, Dublin 2, D02 PN40, Ireland, UK., Katherine A Fitzgerald, 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., Luke A O'Neill, School of biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College, College Green, Dublin 2, D02 PN40, Ireland, UK.,
  • Anne K Hollensen
  • Christian K Damgaard
  • Frank V de Paoli
  • Hanne C Bertram
  • Martin R Jakobsen
  • Thomas B Poulsen
  • Christian K Holm

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.

OriginalsprogEngelsk
TidsskriftNature Communications
Vol/bind9
Tidsskriftsnummer1
Sider (fra-til)3506
ISSN2041-1723
DOI
StatusUdgivet - 29 aug. 2018

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