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

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 Beck Iversen; Lin Lin; Virginia M. Artegoitia; Chenhe Su; Long Yang; Rongtuan Lin; Siddharth Balachandran; Yonglun Luo; Mette Nyegaard; Bernadette Marrero; Raphaela Goldbach-Mansky; M Motwani; 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 Jakobsen; Thomas B. Poulsen; Christian K. Holm

doi:10.1038/s41467-018-05861-7

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

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 Beck Iversen
, Lin Lin
, Virginia M. Artegoitia
, Chenhe Su
, Long Yang
, Rongtuan Lin
, Siddharth Balachandran
, Yonglun Luo

Mette Nyegaard, Bernadette Marrero, Raphaela Goldbach-Mansky, M Motwani, 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 Jakobsen, Thomas B. Poulsen, Christian K. Holm

Research output: Contribution to journal › Article › peer-review

229 Scopus citations

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.

Original language	English
Article number	3506
Pages (from-to)	3506
Journal	Nature Communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-05861-7
State	Published - Dec 1 2018

Keywords

Animals
Cell Line, Tumor
Cells, Cultured
DNA Viruses/metabolism
Gene Expression/drug effects
Humans
Interferon Type I/metabolism
Leukocytes, Mononuclear/immunology
Membrane Proteins/genetics
Mice
NF-E2-Related Factor 2/genetics
RAW 264.7 Cells
RNA, Messenger/metabolism
Succinates/pharmacology

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10.1038/s41467-018-05861-7

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Olagnier, D., Brandtoft, A. M., Gunderstofte, C., Villadsen, N. L., Krapp, C., Thielke, A. L., Laustsen, A., Peri, S., Hansen, A. L., Bonefeld, L., Thyrsted, J., Bruun, V., Iversen, M. B., Lin, L., Artegoitia, V. M., Su, C., Yang, L., Lin, R., Balachandran, S., ... Holm, C. K. (2018). Nrf2 negatively regulates STING indicating a link between antiviral sensing and metabolic reprogramming. Nature Communications, 9(1), 3506. Article 3506. https://doi.org/10.1038/s41467-018-05861-7

@article{111cb25fc0384b93af050397a1b34f6a,

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 = "Animals, Cell Line, Tumor, Cells, Cultured, DNA Viruses/metabolism, Gene Expression/drug effects, Humans, Interferon Type I/metabolism, Leukocytes, Mononuclear/immunology, Membrane Proteins/genetics, Mice, NF-E2-Related Factor 2/genetics, RAW 264.7 Cells, RNA, Messenger/metabolism, Succinates/pharmacology",

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 Beck\} 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 M Motwani and Mona Motwani and Ryan, \{Dylan G.\} and Fitzgerald, \{Katherine A.\} and O{\textquoteright}Neill, \{Luke A.\} and Hollensen, \{Anne K.\} and Damgaard, \{Christian K.\} and \{de Paoli\}, \{Frank v.\} and Bertram, \{Hanne C.\} and Martin Jakobsen and Poulsen, \{Thomas B.\} and Holm, \{Christian K.\}",

note = "Publisher Copyright: {\textcopyright} 2018, The Author(s).",

year = "2018",

month = dec,

day = "1",

doi = "10.1038/s41467-018-05861-7",

language = "English",

volume = "9",

pages = "3506",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

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, Motwani, M, Ryan, DG, Fitzgerald, KA, O’Neill, LA, Hollensen, AK, Damgaard, CK, de Paoli, FV, Bertram, HC, Jakobsen, M, Poulsen, TB & Holm, CK 2018, 'Nrf2 negatively regulates STING indicating a link between antiviral sensing and metabolic reprogramming', Nature Communications, vol. 9, no. 1, 3506, pp. 3506. https://doi.org/10.1038/s41467-018-05861-7

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 Beck

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, M

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

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 - Animals

KW - Cell Line, Tumor

KW - Cells, Cultured

KW - DNA Viruses/metabolism

KW - Gene Expression/drug effects

KW - Humans

KW - Interferon Type I/metabolism

KW - Leukocytes, Mononuclear/immunology

KW - Membrane Proteins/genetics

KW - Mice

KW - NF-E2-Related Factor 2/genetics

KW - RAW 264.7 Cells

KW - RNA, Messenger/metabolism

KW - Succinates/pharmacology

UR - https://www.scopus.com/pages/publications/85052656171

U2 - 10.1038/s41467-018-05861-7

DO - 10.1038/s41467-018-05861-7

M3 - Article

C2 - 30158636

SN - 2041-1723

VL - 9

SP - 3506

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 3506

ER -

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

Abstract

Keywords

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