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Suppressed ubiquitination of Nrf2 by p47phox contributes to Nrf2 activation

Kyun Ha Kim1, Ruxana T Sadikot2, Ji Yeon Lee1

  • 1Division of Applied Medicine, School of Korean Medicine, Pusan National University, Yangsan 50612, Republic of Korea.

Free Radical Biology & Medicine
|September 24, 2017
PubMed

Insights

The NADPH oxidase component p47phox directly activates the antioxidant Nrf2 pathway by binding to it. This interaction protects host cells from damaging reactive oxygen species (ROS) and reduces lung inflammation.

Area of Science:

  • Immunology
  • Cellular Biology
  • Molecular Biology

Background:

  • Reactive oxygen species (ROS) are crucial for phagocytosis but can damage host cells.
  • Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that upregulates antioxidant enzymes to counteract ROS.
  • The activation of Nrf2 by ROS is a key protective mechanism against oxidative stress.

Purpose of the Study:

  • To investigate if NADPH oxidase components, beyond ROS, directly activate Nrf2.
  • To determine the role of specific NADPH oxidase components, particularly p47phox, in Nrf2 activation and cellular protection.

Main Methods:

  • Co-immunoprecipitation assays to assess physical binding between NADPH oxidase components and Nrf2.
  • Western blotting to analyze Nrf2 ubiquitination and nuclear translocation.
  • Quantitative real-time PCR to measure Nrf2-dependent gene expression.
  • In vivo studies using a lipopolysaccharide-induced acute lung inflammation mouse model.

Main Results:

  • p47phox, but not p65phox or p40phox, physically binds to and activates Nrf2.
  • p47phox binding inhibits Nrf2 ubiquitination by Keap1, promoting Nrf2 nuclear translocation and target gene expression.
  • Genetic ablation of p47phox reduces Nrf2-dependent gene expression.
  • In vivo, p47phox expression in lungs suppresses neutrophilic lung inflammation and upregulates Nrf2 targets.

Conclusions:

  • p47phox is a novel direct regulator of Nrf2 function.
  • p47phox activation of Nrf2 provides protection against oxidative damage and inflammation.
Keywords:
Keap1Lung inflammationNADPH oxidaseNrf2Ubiquitinationp47phox

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