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

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

Nature communications (2018-08-31)
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 de Paoli, Hanne C Bertram, Martin R Jakobsen, Thomas B Poulsen, Christian K Holm
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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L-Sulforaphane, ≥95% (HPLC), oil
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