TY - JOUR
T1 - Nrf2 negatively regulates STING indicating a link between antiviral sensing and metabolic reprogramming
AU - Olagnier, David
AU - Brandtoft, Aske M
AU - Gunderstofte, Camilla
AU - Villadsen, Nikolaj L
AU - Krapp, Christian
AU - Thielke, Anne L
AU - Laustsen, Anders
AU - Peri, Suraj
AU - Hansen, Anne Louise
AU - Bonefeld, Lene
AU - Thyrsted, Jacob
AU - Bruun, Victor
AU - Iversen, Marie B
AU - Lin, Lin
AU - Artegoitia, Virginia M
AU - Su, Chenhe
AU - Yang, Long
AU - Lin, Rongtuan
AU - Balachandran, Siddharth
AU - Luo, Yonglun
AU - Nyegaard, Mette
AU - Marrero, Bernadette
AU - Goldbach-Mansky, Raphaela
AU - Motwani, Mona
AU - Ryan, Dylan G
AU - Fitzgerald, Katherine A
AU - O'Neill, Luke A
AU - Hollensen, Anne K
AU - Damgaard, Christian K
AU - de Paoli, Frank V
AU - Bertram, Hanne C
AU - Jakobsen, Martin R
AU - Poulsen, Thomas B
AU - Holm, Christian K
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
KW - ANTIOXIDANT RESPONSE ELEMENT
KW - CYCLIC DINUCLEOTIDE
KW - DENDRITIC CELL-LINE
KW - GENE
KW - INNATE IMMUNITY
KW - PROTEIN
KW - RIG-I
KW - SUCCINATE-DEHYDROGENASE
KW - TRANSCRIPTION FACTOR
KW - VIRUS
UR - http://www.scopus.com/inward/record.url?scp=85052656171&partnerID=8YFLogxK
U2 - 10.1038/s41467-018-05861-7
DO - 10.1038/s41467-018-05861-7
M3 - Journal article
C2 - 30158636
SN - 2041-1723
VL - 9
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 3506
ER -