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

Nature Communications
David OlagnierC 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.

References

Oct 1, 1972·Journal of Bacteriology·M Kato
Dec 2, 2000·Nature·Y IchimuraY Ohsumi
Sep 24, 2005·The Journal of Immunology : Official Journal of the American Association of Immunologists·Stuart A RushworthMaria A O'Connell
Apr 6, 2006·The Journal of Clinical Investigation·Rajesh K ThimmulappaShyam Biswal
Oct 6, 2006·PLoS Medicine·Anju SinghShyam Biswal
Nov 14, 2006·Biochemical and Biophysical Research Communications·Rajesh K ThimmulappaShyam Biswal
Jun 21, 2007·The Journal of Biological Chemistry·Serhiy PankivTerje Johansen
Oct 19, 2007·Journal of Virology·Yueh-Ming LooMichael Gale
Jan 10, 2009·Nature Protocols·Da Wei HuangRichard A Lempicki
Mar 11, 2010·Science Signaling·Gerasimos P Sykiotis, Dirk Bohmann
Oct 29, 2010·Journal of Bioinformatics and Computational Biology·Rune ThomsenAnders Lade Nielsen
Jan 7, 2011·Journal of Virology·Suresh H BasagoudanavarSiddharth Balachandran
Sep 29, 2011·Nature·Dara L BurdetteRussell E Vance
Mar 8, 2012·Science Signaling·Yasuo Tanaka, Zhijian J Chen
Jun 19, 2012·Nature Immunology·Christian K HolmSøren R Paludan
Dec 12, 2012·Nature Biotechnology·Cole TrapnellLior Pachter
Mar 29, 2013·Nature·G M TannahillL A J O'Neill
May 21, 2013·Nature Cell Biology·Ryan C RussellKun-Liang Guan
Oct 12, 2013·PloS One·Suraj PeriSiddharth Balachandran
Mar 22, 2014·Trends in Biochemical Sciences·John D Hayes, Albena T Dinkova-Kostova
May 23, 2014·Nature Communications·Sophia DavidsonAndreas Wack
Jul 17, 2014·The New England Journal of Medicine·Y LiuR Goldbach-Mansky
Nov 18, 2014·The Journal of Clinical Investigation·Nadia JeremiahFrédéric Rieux-Laucat
Dec 18, 2014·Genome Biology·Michael I LoveSimon Anders
Jan 24, 2015·Nature Reviews. Immunology·Finlay McNabAnne O'Garra
Jun 6, 2015·Cell Research·Beth Kelly, Luke A J O'Neill
Nov 10, 2015·Biochemical Society Transactions·Miguel P Soares, Ana M Ribeiro
Feb 20, 2016·Nature Communications·Christian K HolmSøren R Paludan
May 18, 2016·The Journal of Biological Chemistry·Thekla CordesChristian M Metallo
May 24, 2016·Nature Communications·Eri H KobayashiMasayuki Yamamoto
Jul 12, 2016·Nature Reviews. Immunology·Luke A J O'NeillJeff Rathmell
Jul 19, 2016·Autophagy·Marta PajaresAntonio Cuadrado

❮ Previous
Next ❯

Citations

Apr 17, 2019·Journal of Leukocyte Biology·Vijay Kumar
Apr 30, 2020·Carcinogenesis·Feng HeMichael Karin
Jul 15, 2020·The Journal of Clinical Investigation·Marc PfefferléFlorence Vallelian
Aug 14, 2019·Nature Reviews. Cancer·Ferdinandos Skoulidis, John V Heymach
Jul 15, 2020·Life Science Alliance·Brittany L UhlornSamuel K Campos
Jul 10, 2020·International Journal of Molecular Sciences·Feng HeTao Wen
Jun 2, 2020·Frontiers in Oncology·Sandhya ChipurupalliNirmal Robinson
Aug 13, 2020·Nature Reviews. Immunology·Søren R PaludanTrine H Mogensen
Feb 2, 2019·Nature Reviews. Immunology·Luke A J O'Neill, Maxim N Artyomov
Jan 31, 2020·Frontiers in Cellular and Infection Microbiology·Aislan de Carvalho Vivarini, Ulisses Gazos Lopes
Jul 30, 2020·Oxidative Medicine and Cellular Longevity·Ruidong LiKaixong Tao
Jul 3, 2020·Frontiers in Bioengineering and Biotechnology·Xumin LiTim Forouzanfar
Jan 6, 2019·Nature Reviews. Drug Discovery·Antonio CuadradoAlbena T Dinkova-Kostova
Nov 19, 2020·Pigment Cell & Melanoma Research·José Pedro Friedmann Angeli, Svenja Meierjohann
Sep 18, 2020·The Journal of Clinical Investigation·Tolani F OlonisakinJanet S Lee
Oct 29, 2020·Current Opinion in Biotechnology·Jacob Thyrsted, Christian Kanstrup Holm
Jan 1, 2021·Oxidative Medicine and Cellular Longevity·Iara Grigoletto FernandesNátalli Zanete Pereira
Dec 10, 2020·Clinical and Translational Allergy·Jean BousquetUNKNOWN ARIA group
Feb 14, 2021·International Journal of Molecular Sciences·Kristiana M AmirovaMilen I Georgiev
Feb 21, 2021·Current Opinion in Biotechnology·Wei HeKarsten Hiller
Mar 18, 2020·Journal of Thoracic Oncology : Official Publication of the International Association for the Study of Lung Cancer·Jordi RemonGiorgio V Scagliotti
Mar 9, 2021·Frontiers in Immunology·Julia Blay-CadanetChristian Kanstrup Holm
Mar 26, 2021·Cell Death and Differentiation·Miao ZhaoRuimao Zheng
May 8, 2021·Frontiers in Pharmacology·Lingli RenYang Yang
Apr 26, 2020·Molecular Cell·Zbigniew Zasłona, Luke A J O'Neill
Jun 12, 2021·Immunotherapy·Alexander P DavisSteven C Kao
Jun 28, 2021·Reviews in Medical Virology·Goutham V Ganesh, Ramkumar K Mohanram
Jul 3, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Elena GenovaGabriele Stocco

❮ Previous
Next ❯

Methods Mentioned

BETA
RNAseq
immunoprecipitation
ChIP-seq
flow cytometry
transfection
biopsies
FCS
Assay
protein assay
electrophoresis

Clinical Trials Mentioned

NCT02974595

Software Mentioned

DAVID portal
pheatmap
RNAseq
DESeq2
Image J
bigWig
Excel
Active Motifs
MassHunter

Related Concepts

Related Feeds

Antivirals

Antivirals are medications that are used specifically for treating viral infections. Discover the latest research on antivirals here.

Antivirals (ASM)

Antivirals are medications that are used specifically for treating viral infections. Discover the latest research on antivirals here.