An inhibitor of interaction between the transcription factor NRF2 and the E3 ubiquitin ligase adapter β-TrCP delivers anti-inflammatory responses in mouse liver

It is widely accepted that activating the transcription factor NRF2 will blast the physiological anti-inflammatory mechanisms, which will help combat pathologic inflammation. Much effort is being put in inhibiting the main NRF2 repressor, KEAP1, with either electrophilic small molecules or disrupter...

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Detalles Bibliográficos
Autores: Fernández-Ginés, Raquel, Encinar, José Antonio, Hayes, John D., Oliva Miguel, Baldomero, Rodríguez-Franco, Maria Isabel, Rojo, Ana I., Cuadrado, Antonio
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Institución:Universitat Pompeu Fabra
Repositorio:Repositorio Digital de la UPF
OAI Identifier:oai:repositori.upf.edu:10230/54021
Acceso en línea:http://hdl.handle.net/10230/54021
http://dx.doi.org/10.1016/j.redox.2022.102396
Access Level:acceso abierto
Palabra clave:Inflammation
Liver
NRF2
Protein-protein interaction inhibitor
β-TrCP
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spelling An inhibitor of interaction between the transcription factor NRF2 and the E3 ubiquitin ligase adapter β-TrCP delivers anti-inflammatory responses in mouse liverFernández-Ginés, RaquelEncinar, José AntonioHayes, John D.Oliva Miguel, BaldomeroRodríguez-Franco, Maria IsabelRojo, Ana I.Cuadrado, AntonioInflammationLiverNRF2Protein-protein interaction inhibitorβ-TrCPIt is widely accepted that activating the transcription factor NRF2 will blast the physiological anti-inflammatory mechanisms, which will help combat pathologic inflammation. Much effort is being put in inhibiting the main NRF2 repressor, KEAP1, with either electrophilic small molecules or disrupters of the KEAP1/NRF2 interaction. However, targeting β-TrCP, the non-canonical repressor of NRF2, has not been considered yet. After in silico screening of ∼1 million compounds, we now describe a novel small molecule, PHAR, that selectively inhibits the interaction between β-TrCP and the phosphodegron in transcription factor NRF2. PHAR upregulates NRF2-target genes such as Hmox1, Nqo1, Gclc, Gclm and Aox1, in a KEAP1-independent, but β-TrCP dependent manner, breaks the β-TrCP/NRF2 interaction in the cell nucleus, and inhibits the β-TrCP-mediated in vitro ubiquitination of NRF2. PHAR attenuates hydrogen peroxide induced oxidative stress and, in lipopolysaccharide-treated macrophages, it downregulates the expression of inflammatory genes Il1b, Il6, Cox2, Nos2. In mice, PHAR selectively targets the liver and greatly attenuates LPS-induced liver inflammation as indicated by a reduction in the gene expression of the inflammatory cytokines Il1b, TNf, and Il6, and in F4/80-stained liver resident macrophages. Thus, PHAR offers a still unexplored alternative to current NRF2 activators by acting as a β-TrCP/NRF2 interaction inhibitor that may have a therapeutic value against undesirable inflammation.This research was funded by the Spanish Ministry of Economy and Competitiveness (MINECO) (grants PID2019-110061RB-I00, PID2021-122650OB-I00, and PDC2021-121421-I00) and The Autonomous Community of Madrid (grant B2017/BMD-3827). RFG enjoyed FPI contract of MINECO (FPI-2017). The Spanish Ministry of Economy and Competitiveness (MINECO, Project RTI2018-096724-B-C21) and the Generalitat Valenciana (PROMETEO/2021/059) supported the work in the Encinar laboratory.Elsevier202220222022info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/54021http://dx.doi.org/10.1016/j.redox.2022.102396reponame:Repositorio Digital de la UPFinstname:Universitat Pompeu FabraInglésRedox Biol. 2022 Jul 11;55:102396info:eu-repo/grantAgreement/ES/1PE/PID2019-110061RB-I00info:eu-repo/grantAgreement/ES/1PE/RTI2018-096724-B-C21© 2022 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).http://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repositori.upf.edu:10230/540212026-06-12T07:21:37Z
dc.title.none.fl_str_mv An inhibitor of interaction between the transcription factor NRF2 and the E3 ubiquitin ligase adapter β-TrCP delivers anti-inflammatory responses in mouse liver
title An inhibitor of interaction between the transcription factor NRF2 and the E3 ubiquitin ligase adapter β-TrCP delivers anti-inflammatory responses in mouse liver
spellingShingle An inhibitor of interaction between the transcription factor NRF2 and the E3 ubiquitin ligase adapter β-TrCP delivers anti-inflammatory responses in mouse liver
Fernández-Ginés, Raquel
Inflammation
Liver
NRF2
Protein-protein interaction inhibitor
β-TrCP
title_short An inhibitor of interaction between the transcription factor NRF2 and the E3 ubiquitin ligase adapter β-TrCP delivers anti-inflammatory responses in mouse liver
title_full An inhibitor of interaction between the transcription factor NRF2 and the E3 ubiquitin ligase adapter β-TrCP delivers anti-inflammatory responses in mouse liver
title_fullStr An inhibitor of interaction between the transcription factor NRF2 and the E3 ubiquitin ligase adapter β-TrCP delivers anti-inflammatory responses in mouse liver
title_full_unstemmed An inhibitor of interaction between the transcription factor NRF2 and the E3 ubiquitin ligase adapter β-TrCP delivers anti-inflammatory responses in mouse liver
title_sort An inhibitor of interaction between the transcription factor NRF2 and the E3 ubiquitin ligase adapter β-TrCP delivers anti-inflammatory responses in mouse liver
dc.creator.none.fl_str_mv Fernández-Ginés, Raquel
Encinar, José Antonio
Hayes, John D.
Oliva Miguel, Baldomero
Rodríguez-Franco, Maria Isabel
Rojo, Ana I.
Cuadrado, Antonio
author Fernández-Ginés, Raquel
author_facet Fernández-Ginés, Raquel
Encinar, José Antonio
Hayes, John D.
Oliva Miguel, Baldomero
Rodríguez-Franco, Maria Isabel
Rojo, Ana I.
Cuadrado, Antonio
author_role author
author2 Encinar, José Antonio
Hayes, John D.
Oliva Miguel, Baldomero
Rodríguez-Franco, Maria Isabel
Rojo, Ana I.
Cuadrado, Antonio
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv Inflammation
Liver
NRF2
Protein-protein interaction inhibitor
β-TrCP
topic Inflammation
Liver
NRF2
Protein-protein interaction inhibitor
β-TrCP
description It is widely accepted that activating the transcription factor NRF2 will blast the physiological anti-inflammatory mechanisms, which will help combat pathologic inflammation. Much effort is being put in inhibiting the main NRF2 repressor, KEAP1, with either electrophilic small molecules or disrupters of the KEAP1/NRF2 interaction. However, targeting β-TrCP, the non-canonical repressor of NRF2, has not been considered yet. After in silico screening of ∼1 million compounds, we now describe a novel small molecule, PHAR, that selectively inhibits the interaction between β-TrCP and the phosphodegron in transcription factor NRF2. PHAR upregulates NRF2-target genes such as Hmox1, Nqo1, Gclc, Gclm and Aox1, in a KEAP1-independent, but β-TrCP dependent manner, breaks the β-TrCP/NRF2 interaction in the cell nucleus, and inhibits the β-TrCP-mediated in vitro ubiquitination of NRF2. PHAR attenuates hydrogen peroxide induced oxidative stress and, in lipopolysaccharide-treated macrophages, it downregulates the expression of inflammatory genes Il1b, Il6, Cox2, Nos2. In mice, PHAR selectively targets the liver and greatly attenuates LPS-induced liver inflammation as indicated by a reduction in the gene expression of the inflammatory cytokines Il1b, TNf, and Il6, and in F4/80-stained liver resident macrophages. Thus, PHAR offers a still unexplored alternative to current NRF2 activators by acting as a β-TrCP/NRF2 interaction inhibitor that may have a therapeutic value against undesirable inflammation.
publishDate 2022
dc.date.none.fl_str_mv 2022
2022
2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10230/54021
http://dx.doi.org/10.1016/j.redox.2022.102396
url http://hdl.handle.net/10230/54021
http://dx.doi.org/10.1016/j.redox.2022.102396
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Redox Biol. 2022 Jul 11;55:102396
info:eu-repo/grantAgreement/ES/1PE/PID2019-110061RB-I00
info:eu-repo/grantAgreement/ES/1PE/RTI2018-096724-B-C21
dc.rights.none.fl_str_mv http://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:Repositorio Digital de la UPF
instname:Universitat Pompeu Fabra
instname_str Universitat Pompeu Fabra
reponame_str Repositorio Digital de la UPF
collection Repositorio Digital de la UPF
repository.name.fl_str_mv
repository.mail.fl_str_mv
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