Regulation of innate immune responses by NQO1-PDLIM2 axis

• Project/Area Number: 17K08896
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Immunology
• Research Institution: National Center for Global Health and Medicine
• Principal Investigator: Kimura Akihiro 国立研究開発法人国立国際医療研究センター, その他部局等, 室長 (20533318)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: NQO1 / LPS / IL-6 / PDLIM2 / 自然免疫 / Th17細胞 / NAD( P)H：キノン酸化還元酵素 1

Outline of Final Research Achievements

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 on LPS stimulation, and the deletion of NQO1 in macrophages exacerbated LPS-induced septic shock. NQO1 interacted with the nuclear IkB protein IkB-z, which is essential for the TLR-mediated induction of a subset of secondary response genes including IL-6, and promoted IkB-z degradation in a ubiquitin-dependent manner. We identified PDLIM2 as the ubiquitin E3 ligase for NQO1-dependent IkB-z degradation. NQO1 augmented the association between PDLIM2 and IkB-z, resulting in increased IkB-z degradation. Collectively, this study describes a mechanism of the NQO1-PDLIM2 complex as a novel and important ubiquitin E3 ligase.

Academic Significance and Societal Importance of the Research Achievements

敗血症は細菌やウィルスなどの感染症により、全身に炎症が拡がり、進行すると多臓器不全や敗血症ショックといった重篤な病態に陥る。現在、世界で年間2,000万人以上もの人が新たに発症しており、その中のかなりの割合の人が敗血症で亡くなっているとされている。この敗血症を誘発する最初のきっかけとなるのが、TLRと呼ばれる受容体からのシグナル伝達とされている。ところが、TLRシグナルが過剰に伝達されると、IL-6などのサイトカインが多量に産生され敗血症ショックとなる。そのため、TLRシグナルからのIL-6産生制御機構の解明は、敗血症ショックの発症機序の解明やその治療法の確立において非常に重要であるといえる。

Research Products

• [Journal Article] Immunomodulatory mechanism of acyclic nucleoside phosphates in treatment of hepatitis B virus infection. (2019)
  • Author(s): Murata K, Tsukuda S, Suizu F, Kimura A, Sugiyama M, Watashi K, Noguchi M, Mizokami M.
  • Journal Title: Hepatology Volume: 71 Issue: 5 Pages: 1533-1545
  • DOI: 10.1002/hep.30956
  • Peer Reviewed
• [Journal Article] NQO1 inhibits the TLR-dependent production of selective cytokines by promoting IκB-ζ degradation. (2018)
  • Author(s): 1. Kimura, A., Kitajima, M., Nishida, K., Serada, S., Fujimoto, M., Naka, T., Fuji-Kuriyama, Y., Ito, T., Handa, H., Tanaka, T, Yoshimura, A., Suzuki, H.
  • Journal Title: Journal of experimental medicine Volume: 215 Issue: 8 Pages: 2197-2200
  • DOI: 10.1084/jem.20172024
  • Peer Reviewed / Open Access
• [Journal Article] Cutting Edge: Nqo1 Regulates Irritant Contact Hypersensitivity against Croton Oil through Maintenance of Dendritic Epidermal T Cells (2018)
  • Author(s): Kitajima Masayuki、Kimura Akihiro、Suzuki Harumi
  • Journal Title: The Journal of Immunology Volume: 200 Issue: 5 Pages: 1555-1559
  • DOI: 10.4049/jimmunol.1701389
  • Peer Reviewed
• [Presentation] The AhR-sMaf complex promotes the differentiation of Breg cells. (2019)
  • Author(s): Akihiro Kimura and Harumi Suzuki.
  • Organizer: The 48th Annual Meeting of The Japanese Society for Immunology
• [Presentation] The AhR-Arnt-MafK complex regulates the differentiation of regulatory B cells (2018)
  • Author(s): Akihiro Kimura and Harumi Suzuki
  • Organizer: The 47th Annual Meeting of The Japanese Society for Immunology
• [Presentation] The novel ubiquitin ligase complex, NQO1-PDLIM2 inhibits TLR-dependent production of selective cytokines by degrading IkB-z (2017)
  • Author(s): Akihiro Kimura, Masayuki Kitajima and Harumi Suzuki
  • Organizer: The 46th Annual Meeting of The Japanese Society for Immunology
• [Presentation] The novel ubiquitin ligase complex, NQO1-PDLIM2 inhibits TLR-dependent production of selective cytokines by degrading IkB-z (2017)
  • Author(s): Akihiro Kimura, Masayuki Kitajima and Harumi Suzuki
  • Organizer: The 5th Annual Meeting of the International Cytokine and Interferon
  • Int'l Joint Research
• [Remarks] 国立国際医療研究センター 免疫病理研究部
  • URL: http://plaza.umin.ac.jp/~suzukih/cgi-bin/lab/index.cgi