NQO1 inhibits the TLR-dependent production of selective cytokines by promoting IκB-ζ degradation
Year: 2018
Type: article
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.
DOI: 10.1084/jem.20172024
Institutions: National Center for Global Health and Medicine, Tokyo Medical and Dental University, University of Kochi, National Institute of Biomedical Innovation, Health and Nutrition, Kōchi University, Tokyo Institute of Technology, Tokyo Medical University, Japan Science and Technology Agency, RIKEN, RIKEN Center for Integrative Medical Sciences, Keio University
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: hybrid
Awards: G1024352937, Elucidation of the molecular basis of IMiDs' action, Regulation of innate immune responses by NQO1-PDLIM2 axis, Search for novel modulators of cereblon, the target of thalidomide that regulates neural stem cell proliferation and deifferentiation, G4734722005, Exacerbation mechanism of allergic skin inflammation
OpenAlex ID: W2809565633