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 language | English |
|---|---|
| Pages (from-to) | 2197-2209 |
| Number of pages | 13 |
| Journal | Journal of Experimental Medicine |
| Volume | 215 |
| Issue number | 8 |
| DOIs | |
| Publication status | Published - 2018 Sep 1 |
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ASJC Scopus subject areas
- Immunology and Allergy
- Immunology
Cite this
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 journal › Article
}
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.
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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 -