NQO1 inhibits the TLR-dependent production of selective cytokines by promoting I{kappa}B-{zeta} degradation

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 IB protein IB-, which is essential for the TLR-mediated induction of a subset of secondary response genes, including IL-6, and promoted IB- degradation in a ubiquitin-dependent manner. We demonstrated that PDLIM2, known as the ubiquitin E3 ligase, participates in NQO1-dependent IB- degradation. NQO1 augmented the association between PDLIM2 and IB-, resulting in increased IB- 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.

Source: The Journal of Experimental Medicine - August 6, 2018 Category: Internal Medicine Authors: 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. Tags: Innate Immunity and Inflammation Articles Source Type: research