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

Olagnier, David; Motwani, Mona; Fitzgerald, Katherine A.; Holm, Christian K.

dc.contributor.author	Olagnier, David
dc.contributor.author	Motwani, Mona
dc.contributor.author	Fitzgerald, Katherine A.
dc.contributor.author	Holm, Christian K.
dc.date	2022-08-11T08:09:50.000
dc.date.accessioned	2022-08-23T16:45:48Z
dc.date.available	2022-08-23T16:45:48Z
dc.date.issued	2018-08-29
dc.date.submitted	2018-10-04
dc.identifier.citation	<p>Nat Commun. 2018 Aug 29;9(1):3506. doi: 10.1038/s41467-018-05861-7. <a href="https://doi.org/10.1038/s41467-018-05861-7">Link to article on publisher's site</a></p>
dc.identifier.issn	2041-1723 (Linking)
dc.identifier.doi	10.1038/s41467-018-05861-7
dc.identifier.pmid	30158636
dc.identifier.uri	http://hdl.handle.net/20.500.14038/40754
dc.description	<p>Full author list omitted for brevity. For the full list of authors, see article.</p>
dc.description.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.
dc.language.iso	en_US
dc.relation	<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=30158636&dopt=Abstract">Link to Article in PubMed</a></p>
dc.rights	Copyright © The Author(s) 2018. Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
dc.rights.uri	http://creativecommons.org/licenses/by/4.0/
dc.subject	Immunology and Infectious Disease
dc.title	Nrf2 negatively regulates STING indicating a link between antiviral sensing and metabolic reprogramming
dc.type	Journal Article
dc.source.journaltitle	Nature communications
dc.source.volume	9
dc.source.issue	1
dc.identifier.legacyfulltext	https://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=4571&context=oapubs&unstamped=1
dc.identifier.legacycoverpage	https://escholarship.umassmed.edu/oapubs/3559
dc.identifier.contextkey	13014895
refterms.dateFOA	2022-08-23T16:45:48Z
html.description.abstract	<p>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.</p>
dc.identifier.submissionpath	oapubs/3559
dc.contributor.department	Division of Infectious Diseases and Immunology, Department of Medicine
dc.contributor.department	Program in Innate Immunity
dc.source.pages	3506

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Copyright © The Author(s) 2018. Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Except where otherwise noted, this item's license is described as Copyright © The Author(s) 2018. Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.