NQO1 inhibits the TLR-dependent production of selective cytokines by promoting IκB-ζ degradation

Akihiro Kimura, Masayuki Kitajima, Kyoko Nishida, Satoshi Serada, Minoru Fujimoto, Tetsuji Naka, Yoshiaki Fujii-Kuriyama, Satoshi Sakamato, Takumi Ito, Hiroshi Handa, Takashi Tanaka, Akihiko Yoshimura, Harumi Suzuki

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3 Citations (Scopus)

Abstract

NAD(P)H:quinone oxidoreductase 1 (NQO1) protects cells against oxidative stress and toxic quinones. In this study, we found a novel role of NQO1 in suppressing Toll-like receptor (TLR)–mediated innate immune responses. NQO1-deficient macrophages selectively produced excessive amounts of IL-6, IL-12, and GM-CSF on LPS stimulation, and the deletion of NQO1 in macrophages exacerbated LPS-induced septic shock. NQO1 interacted with the nuclear IκB protein IκB-ζ, which is essential for the TLR-mediated induction of a subset of secondary response genes, including IL-6, and promoted IκB-ζ degradation in a ubiquitin-dependent manner. We demonstrated that PDLIM2, known as the ubiquitin E3 ligase, participates in NQO1-dependent IκB-ζ degradation. NQO1 augmented the association between PDLIM2 and IκB-ζ, resulting in increased IκB-ζ degradation. Collectively, this study describes a mechanism of the NQO1–PDLIM2 complex as a novel and important regulator in the innate immune signaling and suggests the therapeutic potential of NQO1 in TLR-mediated inflammation and disorders.

Original languageEnglish
Pages (from-to)2197-2209
Number of pages13
JournalJournal of Experimental Medicine
Volume215
Issue number8
DOIs
Publication statusPublished - 2018 Sep 1

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Kimura, A., Kitajima, M., Nishida, K., Serada, S., Fujimoto, M., Naka, T., Fujii-Kuriyama, Y., Sakamato, S., Ito, T., Handa, H., Tanaka, T., Yoshimura, A., & Suzuki, H. (2018). NQO1 inhibits the TLR-dependent production of selective cytokines by promoting IκB-ζ degradation. Journal of Experimental Medicine, 215(8), 2197-2209. https://doi.org/10.1084/jem.20172024