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

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 Thyrsted, Victor Bruun, Marie B. Iversen, Lin Lin, Virginia M. Artegoitia, Chenhe Su, Long Yang, Rongtuan Lin, Siddharth Balachandran, Yonglun Luo, Mette Nyegaard, Bernadette Marrero, Raphaela Goldbach-Mansky, Mona Motwani, Dylan G. Ryan, Katherine A. Fitzgerald, Luke A. O’Neill, Anne K. Hollensen, Christian K. Damgaard, Frank v. Paoli, Hanne C. Bertram, Martin R. Jakobsen, Thomas B. Poulsen and Christian K. Holm ()
Additional contact information
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
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

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-05861-7

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