Core fucose is critical for CD14-dependent Toll-like receptor 4 signaling.

• Project/Area Number: 26860201
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: General medical chemistry
• Research Institution: Fukushima Medical University (2015-2017); The Institute of Physical and Chemical Research (2014)
• Principal Investigator: IIJIMA Junko 福島県立医科大学, 医学部, 助教 (10559636)
• Project Period (FY): 2014-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2016: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: コアフコース / TLR4 / CD14 / 細胞内輸送 / インターフェロン-β / endocytosis（細胞内への取り込み） / IFN-β / core fucose / endocytosis / 糖鎖 / 糖鎖生物学

Outline of Final Research Achievements

Core fucosylation, a posttranslational modification of N-glycans, modifies several growth factor receptors and impacts on their ligand binding affinity. We suspect that a lack of core fucose affects the Toll-like receptor 4 (Tlr4)-dependent signaling pathway.
Indeed, upon lipopolysaccharide stimulation, Fut8-deficient mouse embryonic fibroblasts (MEFs) produced similar levels of interleukin-6 but markedly reduced levels of interferon-β (IFN-β) compared with wild-type MEFs. Lectin blot analysis of the TLR4 signaling complex revealed that core fucosylation was specifically found on CD14. After lipopolysaccharide stimulation, internalization of TLR4 and CD14 was significantly impaired.
Given that internalized TLR4/ myeloid differentiation factor 2 (MD2) induces IFN-β production, impaired IFN-β production in Fut8-deficient cells is ascribed to impaired TLR4/MD2 internalization. These data show for the first time that glycosylation critically regulates TLR4 signaling.

Research Products

• [Journal Article] Core fucose is critical for CD14-dependent Toll-like receptor 4 signaling. (2017)
  • Author(s): 4.Iijima J, Kobayashi S, Kitazume S*, Kizuka Y, Fujinawa R, Korekane H, Shibata T, Saitoh S, Akashi-Takamura S, Miyake K, Miyoshi E, and Taniguch N
  • Journal Title: Glycobiology Volume: 2017 Pages: 1006-1015
  • DOI: 10.1093/glycob/cwx075
  • Peer Reviewed / Open Access
• [Presentation] Toll様受容体４複合体を介した自然免疫の機能におけるコアフコースの意義 (2015)
  • Author(s): 飯島順子
  • Organizer: BMB2015
  • Place of Presentation: 神戸ポートアイランド
  • Year and Date: 2015-12-01
• [Presentation] Toll様受容体４複合体を介した自然免疫の機能におけるコアフコースの意義 (2015)
  • Author(s): 飯島順子
  • Organizer: Glyco TOKYO2015
  • Place of Presentation: 慶応義塾大学 矢上キャンパス
  • Year and Date: 2015-10-24
• [Remarks] 病原体センサーの機能を変える糖鎖を発見 －コアフコースが自然免疫におけるシグナル伝達経路に必須－
  • URL: http://www.riken.jp/pr/press/2017/20170915_1/