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Nrf2 negatively regulates STING indicating a link between antiviral sensing and metabolic reprogramming.
Olagnier, David; Brandtoft, Aske M; Gunderstofte, Camilla; Villadsen, Nikolaj L; Krapp, Christian; Thielke, Anne L; Laustsen, Anders; Peri, Suraj; Hansen, Anne Louise; Bonefeld, Lene; Thyrsted, Jacob; Bruun, Victor; Iversen, Marie B; Lin, Lin; Artegoitia, Virginia M; Su, Chenhe; Yang, Long; Lin, Rongtuan; Balachandran, Siddharth; Luo, Yonglun; Nyegaard, Mette; Marrero, Bernadette; Goldbach-Mansky, Raphaela; Motwani, Mona; Ryan, Dylan G; Fitzgerald, Katherine A; O'Neill, Luke A; Hollensen, Anne K; Damgaard, Christian K; de Paoli, Frank V; Bertram, Hanne C; Jakobsen, Martin R; Poulsen, Thomas B; Holm, Christian K.
Afiliação
  • Olagnier D; Department of Biomedicine, Aarhus Research Center for Innate Immunology, Aarhus University, Bartholin Alle 6, 8000, Aarhus, Denmark. olagnier@biomed.au.dk.
  • Brandtoft AM; Department of Biomedicine, Aarhus Research Center for Innate Immunology, Aarhus University, Bartholin Alle 6, 8000, Aarhus, Denmark.
  • Gunderstofte C; Department of Biomedicine, Aarhus Research Center for Innate Immunology, Aarhus University, Bartholin Alle 6, 8000, Aarhus, Denmark.
  • Villadsen NL; Department of Chemistry, Aarhus University, Langelandsgade 140, 8000, Aarhus, Denmark.
  • Krapp C; Department of Biomedicine, Aarhus Research Center for Innate Immunology, Aarhus University, Bartholin Alle 6, 8000, Aarhus, Denmark.
  • Thielke AL; Department of Biomedicine, Aarhus Research Center for Innate Immunology, Aarhus University, Bartholin Alle 6, 8000, Aarhus, Denmark.
  • Laustsen A; Department of Biomedicine, Aarhus Research Center for Innate Immunology, Aarhus University, Bartholin Alle 6, 8000, Aarhus, Denmark.
  • Peri S; Fox Chase Cancer Center, 333 Cottman Avenue, Philidelphia, PA, 19111-2497, USA.
  • Hansen AL; Department of Biomedicine, Aarhus Research Center for Innate Immunology, Aarhus University, Bartholin Alle 6, 8000, Aarhus, Denmark.
  • Bonefeld L; Department of Biomedicine, Aarhus Research Center for Innate Immunology, Aarhus University, Bartholin Alle 6, 8000, Aarhus, Denmark.
  • Thyrsted J; Department of Biomedicine, Aarhus Research Center for Innate Immunology, Aarhus University, Bartholin Alle 6, 8000, Aarhus, Denmark.
  • Bruun V; Department of Biomedicine, Aarhus Research Center for Innate Immunology, Aarhus University, Bartholin Alle 6, 8000, Aarhus, Denmark.
  • Iversen MB; Department of Biomedicine, Aarhus Research Center for Innate Immunology, Aarhus University, Bartholin Alle 6, 8000, Aarhus, Denmark.
  • Lin L; Department of Biomedicine, Aarhus Research Center for Innate Immunology, Aarhus University, Bartholin Alle 6, 8000, Aarhus, Denmark.
  • Artegoitia VM; Department of Food Science, Aarhus University, Kirstinebjergvej 10, 5792, Aarslev, Denmark.
  • Su C; Lady Davis Institute-Jewish General Hospital, McGill University, Division of Experimental Medicine, 3755 Côte Ste-Catherine Road, Montreal, QC, H3T 1E2, Canada.
  • Yang L; Lady Davis Institute-Jewish General Hospital, McGill University, Division of Experimental Medicine, 3755 Côte Ste-Catherine Road, Montreal, QC, H3T 1E2, Canada.
  • Lin R; Lady Davis Institute-Jewish General Hospital, McGill University, Division of Experimental Medicine, 3755 Côte Ste-Catherine Road, Montreal, QC, H3T 1E2, Canada.
  • Balachandran S; Fox Chase Cancer Center, 333 Cottman Avenue, Philidelphia, PA, 19111-2497, USA.
  • Luo Y; Department of Biomedicine, Aarhus Research Center for Innate Immunology, Aarhus University, Bartholin Alle 6, 8000, Aarhus, Denmark.
  • Nyegaard M; BGI-Shenzhen, Beishan Industrial Zone, Yantian District, Shenzhen, 518083, China.
  • Marrero B; Department of Biomedicine, Aarhus Research Center for Innate Immunology, Aarhus University, Bartholin Alle 6, 8000, Aarhus, Denmark.
  • Goldbach-Mansky R; Translational Autoinflammatory Diseases Studies, NIAID, NIH, 10 Center Drive, Bethesda, MD, 20892, USA.
  • Motwani M; Translational Autoinflammatory Diseases Studies, NIAID, NIH, 10 Center Drive, Bethesda, MD, 20892, USA.
  • Ryan DG; 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.
  • Fitzgerald KA; School of biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College, College Green, Dublin 2, D02 PN40, Ireland, UK.
  • O'Neill LA; 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.
  • Hollensen AK; School of biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College, College Green, Dublin 2, D02 PN40, Ireland, UK.
  • Damgaard CK; Department of Molecular Biology and Genetics, Aarhus University, C.F. Moellers Allé 3, 8000, Aarhus, Denmark.
  • de Paoli FV; Department of Molecular Biology and Genetics, Aarhus University, C.F. Moellers Allé 3, 8000, Aarhus, Denmark.
  • Bertram HC; Department of Biomedicine, Aarhus Research Center for Innate Immunology, Aarhus University, Bartholin Alle 6, 8000, Aarhus, Denmark.
  • Jakobsen MR; Department of Food Science, Aarhus University, Kirstinebjergvej 10, 5792, Aarslev, Denmark.
  • Poulsen TB; Department of Biomedicine, Aarhus Research Center for Innate Immunology, Aarhus University, Bartholin Alle 6, 8000, Aarhus, Denmark.
  • Holm CK; Department of Chemistry, Aarhus University, Langelandsgade 140, 8000, Aarhus, Denmark.
Nat Commun ; 9(1): 3506, 2018 08 29.
Article em En | MEDLINE | ID: mdl-30158636
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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fator 2 Relacionado a NF-E2 / Proteínas de Membrana Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: Nat Commun Assunto da revista: BIOLOGIA / CIENCIA Ano de publicação: 2018 Tipo de documento: Article País de afiliação: Dinamarca

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fator 2 Relacionado a NF-E2 / Proteínas de Membrana Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: Nat Commun Assunto da revista: BIOLOGIA / CIENCIA Ano de publicação: 2018 Tipo de documento: Article País de afiliação: Dinamarca