Department of Immunology and Pathology, Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine, Chiba, Japan.
Department of Immunology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
J Exp Med. 2018 Aug 6;215(8):2197-2209. doi: 10.1084/jem.20172024. Epub 2018 Jun 22.
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.
NAD(P)H:醌氧化还原酶 1（NQO1）可保护细胞免受氧化应激和有毒醌类物质的侵害。在这项研究中，我们发现了 NQO1 在抑制 Toll 样受体（TLR）介导的先天免疫反应中的新作用。NQO1 缺陷型巨噬细胞在 LPS 刺激下选择性地产生大量的 IL-6、IL-12 和 GM-CSF，而巨噬细胞中 NQO1 的缺失加剧了 LPS 诱导的败血症休克。NQO1 与核 IκB 蛋白 IκB-ζ相互作用，IκB-ζ 对于 TLR 介导的一组次要反应基因的诱导至关重要，包括 IL-6，并以依赖泛素的方式促进 IκB-ζ 降解。我们证明了 PDLIM2（已知是泛素 E3 连接酶）参与了 NQO1 依赖性 IκB-ζ 降解。NQO1 增强了 PDLIM2 和 IκB-ζ 之间的关联，导致 IκB-ζ 降解增加。总之，这项研究描述了 NQO1-PDLIM2 复合物作为先天免疫信号的新的和重要调节剂的机制，并提示了 NQO1 在 TLR 介导的炎症和疾病中的治疗潜力。
