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

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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.

I: Nature Communications, Bind 9, Nr. 1, 3506, 29.08.2018.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

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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. / Nrf2 negatively regulates STING indicating a link between antiviral sensing and metabolic reprogramming. I: Nature Communications. 2018 ; Bind 9, Nr. 1.

Bibtex

@article{df1ceb14e1c84afbb073b629f0759d17,
title = "Nrf2 negatively regulates STING indicating a link between antiviral sensing and metabolic reprogramming",
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.",
keywords = "ANTIOXIDANT RESPONSE ELEMENT, CYCLIC DINUCLEOTIDE, DENDRITIC CELL-LINE, GENE, INNATE IMMUNITY, PROTEIN, RIG-I, SUCCINATE-DEHYDROGENASE, TRANSCRIPTION FACTOR, VIRUS",
author = "David Olagnier and Brandtoft, {Aske M} and Camilla Gunderstofte and Villadsen, {Nikolaj L} and Christian Krapp and Thielke, {Anne L} and Anders Laustsen and Suraj Peri and Hansen, {Anne Louise} and Lene Bonefeld and Jacob Thyrsted and Victor Bruun and Iversen, {Marie B} and Lin Lin and Artegoitia, {Virginia M} and Chenhe Su and Long Yang and Rongtuan Lin and Siddharth Balachandran and Yonglun Luo and Mette Nyegaard and Bernadette Marrero and Raphaela Goldbach-Mansky and Mona Motwani and Ryan, {Dylan G} and Fitzgerald, {Katherine A} and O'Neill, {Luke A} and Hollensen, {Anne K} and Damgaard, {Christian K} and {de Paoli}, {Frank V} and Bertram, {Hanne C} and Jakobsen, {Martin R} and Poulsen, {Thomas B} and Holm, {Christian K}",
year = "2018",
month = aug,
day = "29",
doi = "10.1038/s41467-018-05861-7",
language = "English",
volume = "9",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",

}

RIS

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 - 2018/8/29

Y1 - 2018/8/29

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

U2 - 10.1038/s41467-018-05861-7

DO - 10.1038/s41467-018-05861-7

M3 - Journal article

C2 - 30158636

VL - 9

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 3506

ER -