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; Encinar, José Antonio; Hayes, John D.; Oliva Miguel, Baldomero; Rodríguez-Franco, Maria Isabel; Rojo, Ana I.; Cuadrado, Antonio

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

Mostra el registre complet Registre parcial de l'ítem

dc.contributor.author Fernández-Ginés, Raquel
dc.contributor.author Encinar, José Antonio
dc.contributor.author Hayes, John D.
dc.contributor.author Oliva Miguel, Baldomero
dc.contributor.author Rodríguez-Franco, Maria Isabel
dc.contributor.author Rojo, Ana I.
dc.contributor.author Cuadrado, Antonio
dc.date.accessioned 2022-09-08T06:04:48Z
dc.date.available 2022-09-08T06:04:48Z
dc.date.issued 2022
dc.description.abstract 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.
dc.description.sponsorship 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.
dc.format.mimetype application/pdf
dc.identifier.citation Fernández-Ginés R, Encinar JA, Hayes JD, Oliva B, Rodríguez-Franco MI, Rojo AI, Cuadrado A. An inhibitor of interaction between the transcription factor NRF2 and the E3 ubiquitin ligase adapter β-TrCP delivers anti-inflammatory responses in mouse liver. Redox Biol. 2022 Jul 11;55:102396. DOI: 10.1016/j.redox.2022.102396
dc.identifier.doi http://dx.doi.org/10.1016/j.redox.2022.102396
dc.identifier.issn 2213-2317
dc.identifier.uri http://hdl.handle.net/10230/54021
dc.language.iso eng
dc.publisher Elsevier
dc.relation.ispartof Redox Biol. 2022 Jul 11;55:102396
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/PID2019-110061RB-I00
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/RTI2018-096724-B-C21
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.subject.keyword Inflammation
dc.subject.keyword Liver
dc.subject.keyword NRF2
dc.subject.keyword Protein-protein interaction inhibitor
dc.subject.keyword β-TrCP
dc.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
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/publishedVersion

Col·leccions

Articles (Departament de Medicina i Ciències de la Vida)
Articles (Hospital del Mar Research Institute)