Inflammatory response regulation by immune system specific autophagy regulator Rufy4

• Project/Area Number: 18K06937
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 48040:Medical biochemistry-related
• Research Institution: Osaka City University
• Principal Investigator: TERAWAKI Seigo 大阪市立大学, 大学院医学研究科, 助教 (60437217)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: オートファジー / メンブレントラフィッキング / NETosis / 炎症性疾患 / 分子免疫制御 / 炎症応答 / 免疫応答制御 / 炎症 / ユビキチン / シグナル伝達 / メンブレントラフィック

Outline of Final Research Achievements

To elucidate the pathophysiological function of immune system-specific autophagy regulator Rufy4 which is constantly expressed in neutrophil, we investigated the involvement of Rufy4 in NETosis progression. Non-inflammatory neutrophils are isolated from wild type, or rufy4-deficient mice peritoneal wash by density-gradient centrifugation. Although NETosis was induced both in wild type and rufy4 deficient neutrophils, NETs expelled from rufy4 KO neutrophil was drastically reduced as compared to wild type. This result suggested that Rufy4 has a critical role in NETosis progression, but not in initiation.

Academic Significance and Societal Importance of the Research Achievements

好中球は感染初期における生体防御を担っており、感染の負荷が高い場合にはNETosisとよばれる細胞死を誘導し、分泌顆粒内の消化酵素とともに自らのクロマチンDNAを放出して細菌を物理的に捕捉殺菌していることが知られているが、その分子メカニズムはまだ不明な点が多い。本研究において免疫系特異的オートファジー制御因子であるRufy4がNETosisの進行に重要な機能を持っていることが示唆された。NETosisは自己免疫疾患や血管炎、さらにはCOPDやCOVID-19など炎症性肺疾患への関与も指摘されており、本研究はこれら難治性炎症疾患の病態解明や治療法開発に繋がることが期待される。

Research Products

• [Journal Article] Th2 cells and macrophages cooperatively induce allergic inflammation through histamine signaling (2021)
  • Author(s): Iwasaki N, Terawaki S, Shimizu K, Oikawa D, Sakamoto H, Sunami K, Tokunaga F.
  • Journal Title: Plos One Volume: - Issue: 3 Pages: e0248158-e0248158
  • DOI: 10.1371/journal.pone.0248158
  • Peer Reviewed / Open Access
• [Journal Article] Crosstalk Between NDP52 and LUBAC in Innate Immune Responses, Cell Death, and Xenophagy. (2021)
  • Author(s): Miyashita H, Oikawa D, Terawaki S, Kabata D, Shintani A, Tokunaga F.
  • Journal Title: Frontiers in Immunology Volume: 12 Pages: 635475-635475
  • DOI: 10.3389/fimmu.2021.635475
  • Peer Reviewed / Open Access
• [Journal Article] Th2 cell-derived histamine is involved in nasal Th2 infiltration in mice (2021)
  • Author(s): Iwasaki N, Terawaki S, Shimizu K, Oikawa D, Sakamoto H, Sunami K, Tokunaga F.
  • Journal Title: Inflammation Research Volume: In press Issue: 5 Pages: 539-541
  • DOI: 10.1007/s00011-021-01458-x
  • Peer Reviewed / Open Access
• [Journal Article] Molecular bases for HOIPINs-mediated inhibition of LUBAC and innate immune responses. (2020)
  • Author(s): Oikawa D, Sato Y, Ohtake F, Komakura K, Hanada K, Sugawara K, Terawaki S, Mizukami Y, Phuong HT, Iio K, Obika S, Fukushi M, Irie T, Tsuruta D, Sakamoto S, Tanaka K, Saeki Y, Fukai S, Tokunaga F.
  • Journal Title: Commun. Biol. Volume: 3 Issue: 1 Pages: 163-163
  • DOI: 10.1038/s42003-020-0882-8
  • Peer Reviewed / Open Access
• [Journal Article] LC3 lipidation is essential for TFEB activation during the lysosomal damage response to kidney injury (2020)
  • Author(s): Shuhei Nakamura et al.,
  • Journal Title: Nature Cell Biology Volume: 22 Issue: 10 Pages: 1252-1263
  • DOI: 10.1038/s41556-020-00583-9
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] NDP52のユビキチン結合性を介した炎症応答・細胞死制御とLUBAC阻害剤の影響 (2020)
  • Author(s): 宮下 裕久, 及川 大輔, 寺脇 正剛, 徳永 文稔
  • Organizer: 第93回 日本生化学会大会
• [Presentation] Macrophages produce histamine through the interaction with antigen specific Th2 cells (2020)
  • Author(s): Naruhito Iwasaki, Seigo Terawaki, Hirokazu Sakamoto, Kishiko Sunami, Fuminori Tokunaga
  • Organizer: 第69回 日本アレルギー学会学術大会
• [Presentation] HOIPIN-1, a novel LUBAC inhibitor, suppresses the imiquimod-induced psoriasis-like skin inflammation in mice (2019)
  • Author(s): Komakura K., Oikawa D., Terawaki S., Sakamoto S., Mizukami Y., Sugawara K., Tsuruta D., Tokunaga F.
  • Organizer: Society for Investigative Dermatology 77th Annual Meeting
  • Int'l Joint Research