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

Raquel Fernández-Ginés, José Antonio Encinar, John D. Hayes, Baldo Oliva, Maria Isabel Rodríguez-Franco, Ana I. Rojo, Antonio Cuadrado (Lead / Corresponding author)

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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.

Original languageEnglish
Article number102396
Number of pages17
JournalRedox Biology
Volume55
Early online date11 Jul 2022
DOIs
Publication statusPublished - Sep 2022

Keywords

  • Inflammation
  • Liver
  • NRF2
  • Protein-protein interaction inhibitor
  • β-TrCP

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