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Olagnier D , Brandtoft AM , Gunderstofte C , Villadsen NL , Krapp C , Thielke AL , Laustsen A , Peri S , Hansen AL , Bonefeld L , Thyrsted J , Bruun V , Iversen MB , Lin L , Artegoitia VM , Su C , Yang L , Lin R , Balachandran S , Luo Y , Nyegaard M , Marrero B , Goldbach-Mansky R , Motwani M , Ryan DG , Fitzgerald KA , O'Neill LA , Hollensen AK , Damgaard CK , de Paoli FV , Bertram HC , Jakobsen MR , Poulsen TB , Holm CK
Nrf2 negatively regulates STING indicating a link between antiviral sensing and metabolic reprogramming
Nat Commun. 2018 Aug 29;9(1) :3506
PMID: 30158636    PMCID: PMC6115435   
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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.
Notes
2041-1723 Olagnier, David Brandtoft, Aske M ORCID: http://orcid.org/0000-0003-1086-0023 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 ORCID: http://orcid.org/0000-0001-5469-8908 Su, Chenhe Yang, Long Lin, Rongtuan Balachandran, Siddharth Luo, Yonglun ORCID: http://orcid.org/0000-0002-0007-7759 Nyegaard, Mette ORCID: http://orcid.org/0000-0002-2967-6624 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 ORCID: http://orcid.org/0000-0001-8847-9201 Poulsen, Thomas B Holm, Christian K Journal Article England Nat Commun. 2018 Aug 29;9(1):3506. doi: 10.1038/s41467-018-05861-7.