An inhibitor of interaction between the transcription factor NRF2 and the E3 ubiquitin ligase adapter ß-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...
| Autores: | , , , , , , |
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| Formato: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2022 |
| País: | España |
| Recursos: | Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (FISABIO) |
| Repositorio: | r-FISABIO. Repositorio Institucional de Producción Científica |
| OAI Identifier: | oai:dnet:r-fisabio___::2f5bea07706cdf7b6a7d76e426a3d156 |
| Acesso em linha: | https://fisabio.portalinvestigacion.com/publicaciones/20865 |
| Access Level: | acceso abierto |
| Palavra-chave: | NRF2 beta-TrCP Protein-protein interaction inhibitor Inflammation Liver |
| Resumo: | 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 beta-TrCP, the non-canonical repressor of NRF2, has not been considered yet. After in silico screening of similar to 1 million compounds, we now describe a novel small molecule, PHAR, that selectively inhibits the interaction between beta-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 beta-TrCP dependent manner, breaks the beta-TrCP/NRF2 interaction in the cell nucleus, and inhibits the beta-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 beta-TrCP/NRF2 interaction inhibitor that may have a therapeutic value against undesirable inflammation. |
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