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Author Notes:

Myungsoo Joo Division of Applied Medicine, School of Korean Medicine, Pusan National University, Yangsan 50612, Republic of Korea Email: mjoo@pusan.ac.kr

We thank Dr. Michael Freeman at Vanderbilt University School of Medicine for the generous support for this study.

The authors declare no competing financial interest in relation to the study.

Subjects:

Research Funding:

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (2014R1A5A2009936).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Biochemistry & Molecular Biology
  • Endocrinology & Metabolism
  • Nrf2
  • p47phox
  • NADPH oxidase
  • Keap1
  • Ubiquitination
  • Lung inflammation
  • CHRONIC GRANULOMATOUS-DISEASE
  • NADPH OXIDASE
  • OXIDATIVE STRESS
  • GENE-EXPRESSION
  • NEUTROPHIL RECRUITMENT
  • IMMUNE-RESPONSE
  • LUNG INJURY
  • NOX-FAMILY
  • MACROPHAGES
  • MICE

Suppressed ubiquitination of Nrf2 by p47phox contributes to Nrf2 activation

Tools:

Journal Title:

Free Radical Biology and Medicine

Volume:

Volume 113

Publisher:

, Pages 48-58

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Although critical in phagocytosis in innate immunity, reactive oxygen species (ROS) collaterally inflict damage to host phagocytes because they indiscriminate targets. Since Nrf2 increases the expression of anti-oxidant enzymes that nullifies ROS, ROS activating Nrf2 is a critical negative regulatory step for countering the deleterious effects of ROS. Here, we postulate whether, along with ROS activating Nrf2, NADPH oxidase components also participate in direct activation of Nrf2, contributing to protection from ROS. Our results show that the p47 phox of the NADPH oxidase, but not p65 phox or p40 phox , physically binds to Nrf2, activating the Nrf2 function. p47 phox binding to Nrf2/Keap1 complex suppresses the ubiquitination of Nrf2, while p47 phox becomes ubiquitinated by Keap1. p47 phox increases the nuclear translocation of Nrf2 and the expression of Nrf2-dependent genes, whereas genetic ablation of p47 phox decreases the expression of those genes. In a lipopolysaccharide-induced acute lung inflammation mouse model, selective expression of p47 phox in mouse lungs induces the expression of Nrf2-dependent genes and is sufficient to suppress neutrophilic lung inflammation. Therefore, our findings suggest that p47 phox is a novel regulator of Nrf2 function.

Copyright information:

© 2017 Elsevier Inc.

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