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

Research output: Contribution to journalArticle

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

Fingerprint

Toll-Like Receptors
Cytokines
Interleukin-6
Macrophages
Quinones
Ubiquitin-Protein Ligases
Poisons
Interleukin-12
Granulocyte-Macrophage Colony-Stimulating Factor
Septic Shock
Nuclear Proteins
Ubiquitin
Innate Immunity
NAD
Oxidoreductases
Oxidative Stress
Inflammation
Genes
Therapeutics

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Kimura, A., Kitajima, M., Nishida, K., Serada, S., Fujimoto, M., Naka, T., ... 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

NQO1 inhibits the TLR-dependent production of selective cytokines by promoting IκB-ζ degradation. / Kimura, Akihiro; Kitajima, Masayuki; Nishida, Kyoko; Serada, Satoshi; Fujimoto, Minoru; Naka, Tetsuji; Fujii-Kuriyama, Yoshiaki; Sakamato, Satoshi; Ito, Takumi; Handa, Hiroshi; Tanaka, Takashi; Yoshimura, Akihiko; Suzuki, Harumi.

In: Journal of Experimental Medicine, Vol. 215, No. 8, 01.09.2018, p. 2197-2209.

Research output: Contribution to journalArticle

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, vol. 215, no. 8, pp. 2197-2209. https://doi.org/10.1084/jem.20172024
Kimura, Akihiro ; Kitajima, Masayuki ; Nishida, Kyoko ; Serada, Satoshi ; Fujimoto, Minoru ; Naka, Tetsuji ; Fujii-Kuriyama, Yoshiaki ; Sakamato, Satoshi ; Ito, Takumi ; Handa, Hiroshi ; Tanaka, Takashi ; Yoshimura, Akihiko ; Suzuki, Harumi. / NQO1 inhibits the TLR-dependent production of selective cytokines by promoting IκB-ζ degradation. In: Journal of Experimental Medicine. 2018 ; Vol. 215, No. 8. pp. 2197-2209.
@article{8cab4a89392b44acb5b7418a56d19c0e,
title = "NQO1 inhibits the TLR-dependent production of selective cytokines by promoting IκB-ζ degradation",
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.",
author = "Akihiro Kimura and Masayuki Kitajima and Kyoko Nishida and Satoshi Serada and Minoru Fujimoto and Tetsuji Naka and Yoshiaki Fujii-Kuriyama and Satoshi Sakamato and Takumi Ito and Hiroshi Handa and Takashi Tanaka and Akihiko Yoshimura and Harumi Suzuki",
year = "2018",
month = "9",
day = "1",
doi = "10.1084/jem.20172024",
language = "English",
volume = "215",
pages = "2197--2209",
journal = "Journal of Experimental Medicine",
issn = "0022-1007",
publisher = "Rockefeller University Press",
number = "8",

}

TY - JOUR

T1 - NQO1 inhibits the TLR-dependent production of selective cytokines by promoting IκB-ζ degradation

AU - Kimura, Akihiro

AU - Kitajima, Masayuki

AU - Nishida, Kyoko

AU - Serada, Satoshi

AU - Fujimoto, Minoru

AU - Naka, Tetsuji

AU - Fujii-Kuriyama, Yoshiaki

AU - Sakamato, Satoshi

AU - Ito, Takumi

AU - Handa, Hiroshi

AU - Tanaka, Takashi

AU - Yoshimura, Akihiko

AU - Suzuki, Harumi

PY - 2018/9/1

Y1 - 2018/9/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85054719202&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85054719202&partnerID=8YFLogxK

U2 - 10.1084/jem.20172024

DO - 10.1084/jem.20172024

M3 - Article

VL - 215

SP - 2197

EP - 2209

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

SN - 0022-1007

IS - 8

ER -