Characterization of multifunctional roles of TRAF5 in pro-inflammatory cytokine receptor signaling

• Project/Area Number: 18H02572
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 47030:Pharmaceutical hygiene and biochemistry-related
• Research Institution: University of Toyama
• Principal Investigator: SO Takanori 富山大学, 学術研究部薬学・和漢系, 教授 (60294964)
• Co-Investigator(Kenkyū-buntansha): 守田 雅志 富山大学, 学術研究部薬学・和漢系, 准教授 (20191033) ; 石井 直人 東北大学, 医学系研究科, 教授 (60291267) ; 川口 甲介 富山大学, 学術研究部薬学・和漢系, 助教 (80624866)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2020: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2019: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2018: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
• Keywords: 免疫 / 炎症 / サイトカイン / TRAF / シグナル伝達

Outline of Final Research Achievements

In this study, we found novel roles of TRAF5 in immunity and inflammation: 1) negative regulatory function of TRAF5 in signaling mediated by receptors for IL-6 and IL-27, 2) significance of TRAF5 in differentiation and effector function of plasmacytoid dendritic cells, 3) inflammatory function of TRAF5 in lung inflammation mediated by OSM, 4) inflammatory function of TRAF5 in colonic inflammation mediated by DSS. These results indicate that TRAF5 expressed by different cell types controls inflammatory signaling in both positive and negative ways. Further study is essential to understand the regulatory roles of TRAF5 and its family molecules in health and diseases.

Academic Significance and Societal Importance of the Research Achievements

老化により炎症性疾患の頻度が増加することから、その根底に存在する炎症のしくみを理解することは、超高齢社会を迎えた日本で非常に重要な課題である。炎症応答で体内の様々な細胞から産生される代表的な炎症性サイトカインTNF、IL-6、IL-1とこれらのファミリー分子群の作用は、炎症性疾患の病態と密接に関連する。本研究で、TRAF5がIL-6、IL-27、OSM、TNF-αの受容体やTLRのシグナル伝達に関連することで、炎症や免疫応答を制御する新しい機序を明らかにした。

Research Products

• [Journal Article] Bone marrow transplantation into Abcd1‐deficient mice: Distribution of donor derived‐cells and biological characterization of the brain of the recipient mice (2021)
  • Author(s): Morita Masashi、Kaizawa Taro、Yoda Taiki、Oyama Takuro、Asakura Reina、Matsumoto Shun、Nagai Yoshinori、Watanabe Yasuharu、Watanabe Shiro、Kobayashi Hiroshi、Kawaguchi Kosuke、Yamamoto Seiji、Shimozawa Nobuyuki、So Takanori、Imanaka Tsuneo
  • Journal Title: Journal of Inherited Metabolic Disease Volume: 44 Issue: 3 Pages: 718-727
  • DOI: 10.1002/jimd.12346
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Acyl-CoA thioesterase activity of peroxisomal ABC protein ABCD1 is required for the transport of very long-chain acyl-CoA into peroxisomes (2021)
  • Author(s): Kawaguchi Kosuke、Mukai Emi、Watanabe Shiro、Yamashita Atsushi、Morita Masashi、So Takanori、Imanaka Tsuneo
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 2192-2192
  • DOI: 10.1038/s41598-021-81949-3
  • Peer Reviewed / Open Access
• [Journal Article] Generation of an immortalized astrocytic cell line from Abcd1-deficient H-2KbtsA58 mice to facilitate the study of the role of astrocytes in X-linked adrenoleukodystrophy (2021)
  • Author(s): Morita Masashi、Toida Ai、Horiuchi Yuki、Watanabe Shiro、Sasahara Masakiyo、Kawaguchi Kosuke、So Takanori、Imanaka Tsuneo
  • Journal Title: Heliyon Volume: 7 Issue: 2 Pages: e06228-e06228
  • DOI: 10.1016/j.heliyon.2021.e06228
  • Peer Reviewed / Open Access
• [Journal Article] Functional Analysis of the Transcriptional Regulator IκB-ζ in Intestinal Homeostasis (2021)
  • Author(s): Sasaki Tomoki、Nagashima Hiroyuki、Okuma Atsushi、Yamauchi Takeshi、Yamasaki Kenshi、Aiba Setsuya、So Takanori、Ishii Naoto、Owada Yuji、MaruYama Takashi、Kobayashi Shuhei
  • Journal Title: Digestive Diseases and Sciences Volume: - Issue: 4 Pages: 1252-1259
  • DOI: 10.1007/s10620-021-06958-8
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The lysosomal protein ABCD4 can transport vitamin B12 across liposomal membranes in?vitro (2021)
  • Author(s): Kitai Katsuki、Kawaguchi Kosuke、Tomohiro Takenori、Morita Masashi、So Takanori、Imanaka Tsuneo
  • Journal Title: Journal of Biological Chemistry Volume: 296 Pages: 100654-100654
  • DOI: 10.1016/j.jbc.2021.100654
  • Peer Reviewed / Open Access
• [Journal Article] GITR controls intestinal inflammation by suppressing IL-15-dependent NK cell activity. (2020)
  • Author(s): Sakurai T, Okuyama Y, Kobayashi S, Phung HT, Asao A, Kawabe T, Ndhlovu LC, Riccardi C, Kudo H, Wada M, Nio M, So T, Ishii N.
  • Journal Title: FASEB J. Volume: 34(11) Issue: 11 Pages: 14820-14831
  • DOI: 10.1096/fj.202001675r
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] TRAF5 promotes plasmacytoid dendritic cell development from bone marrow progenitors (2020)
  • Author(s): Kobayashi Shuhei、Shiota Yuka、Kawabe Takeshi、Phung Hai The、Maruyama Takashi、Owada Yuji、So Takanori、Ishii Naoto
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 521 Issue: 2 Pages: 353-359
  • DOI: 10.1016/j.bbrc.2019.10.123
  • Peer Reviewed
• [Journal Article] TRAF5 Deficiency Ameliorates the Severity of Dextran Sulfate Sodium Colitis by Decreasing TRAF2 Expression in Nonhematopoietic Cells (2020)
  • Author(s): Phung Hai The、Nagashima Hiroyuki、Kobayashi Shuhei、Asano Naoki、Machiyama Tomoaki、Sakurai Tsuyoshi、Tayama Shun-ichi、Asao Atsuko、Imatani Akira、Kawabe Takeshi、Okuyama Yuko、Ishii Naoto、So Takanori
  • Journal Title: ImmunoHorizons Volume: 4 Issue: 3 Pages: 129-139
  • DOI: 10.4049/immunohorizons.2000007
  • Peer Reviewed / Open Access
• [Journal Article] TNF Receptor-Associated Factor 5 Limits Function of Plasmacytoid Dendritic Cells by Controlling IFN Regulatory Factor 5 Expression (2019)
  • Author(s): Kobayashi Shuhei、Sakurai Tsuyoshi、So Takanori、Shiota Yuka、Asao Atsuko、Phung Hai The、Tanaka Riou、Kawabe Takeshi、Maruyama Takashi、Kanno Emi、Kawakami Kazuyoshi、Owada Yuji、Ishii Naoto
  • Journal Title: The Journal of Immunology Volume: 203 Issue: 6 Pages: 1447-1456
  • DOI: 10.4049/jimmunol.1900188
  • Peer Reviewed / Open Access
• [Journal Article] IQ motif-containing GTPase-activating protein 1 is essential for the optimal maintenance of lung ILC2s (2019)
  • Author(s): Tayama Shunichi、Okuyama Yuko、Phung Hai The、Asao Atsuko、Kobayashi Shuhei、Musha Tomomi、Machiyama Tomoaki、Sakurai Tsuyoshi、Zhang Chengming、Ushio-Fukai Masuko、Kawabe Takeshi、So Takanori、Ishii Naoto
  • Journal Title: International Immunology Volume: - Issue: 4 Pages: 233-241
  • DOI: 10.1093/intimm/dxz077
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] IQGAP1 restrains T‐cell cosignaling mediated by OX40 (2019)
  • Author(s): Okuyama Yuko、Nagashima Hiroyuki、Ushio‐Fukai Masuko、Croft Michael、Ishii Naoto、So Takanori
  • Journal Title: The FASEB Journal Volume: 34 Issue: 1 Pages: 540-554
  • DOI: 10.1096/fj.201900879rr
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Biallelic variants/mutations of IL1RAP in patients with steroid-sensitive nephrotic syndrome (2019)
  • Author(s): Niitsuma Sou、Kudo Hiroki、Kikuchi Atsuo、Hayashi Takaya、Kumakura Satoshi、Kobayashi Shuhei、Okuyama Yuko、Kumagai Naonori、Niihori Tetsuya、Aoki Yoko、So Takanori、Funayama Ryo、Nakayama Keiko、Shirota Matsuyuki、Kondo Shuji、Kagami Shoji、Tsukaguchi Hiroyasu、Iijima Kazumoto、Kure Shigeo、Ishii Naoto
  • Journal Title: International Immunology Volume: 32 Issue: 4 Pages: 283-292
  • DOI: 10.1093/intimm/dxz081
  • Peer Reviewed / Open Access
• [Journal Article] GITR cosignal in ILC2s controls allergic lung inflammation. (2018)
  • Author(s): Nagashima H, Okuyama Y, Fujita T, Takeda T, Motomura Y, Moro K, Hidaka T, Omori K, Sakurai T, Machiyama T, Ndhlovu LC, Riccardi C, So T, Ishii N.
  • Journal Title: J Allergy Clin Immunol. Volume: - Issue: 5 Pages: 1939-1943.e8
  • DOI: 10.1016/j.jaci.2018.01.028
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] TNF receptor associated factor 5 controls oncostatin M-mediated lung inflammation. (2018)
  • Author(s): Machiyama T, So T, Okuyama Y, Kobayashi S, Phung HT, Asao A, Harigae H, Ishii N.
  • Journal Title: Biochem Biophys Res Commun. Volume: - Issue: 3 Pages: 544-550
  • DOI: 10.1016/j.bbrc.2018.03.186
  • Peer Reviewed
• [Journal Article] TRAF2 and TRAF5 associated with the signal transducing receptor gp130 limit IL-6-driven transphosphorylation of JAK1 through the inhibition of proximal JAK-JAK interaction. (2018)
  • Author(s): Kimura M, Nagashima H, Okuyama Y, Ishii N, and So T
  • Journal Title: Int. Immunol Volume: - Issue: 7 Pages: 219-299
  • DOI: 10.1093/intimm/dxy029
  • Peer Reviewed
• [Journal Article] Regulation of Interleukin-6 Receptor Signaling by TNF Receptor-Associated Factor 2 and 5 During Differentiation of Inflammatory CD4+ T Cells (2018)
  • Author(s): Nagashima Hiroyuki、Ishii Naoto、So Takanori
  • Journal Title: Frontiers in Immunology Volume: 9 Pages: 1986-1986
  • DOI: 10.3389/fimmu.2018.01986
  • Peer Reviewed / Open Access
• [Presentation] TRAF5 による CD4+ T 細胞の IL-27 受容体シグナル調節機構 (2021)
  • Author(s): 河原 永悟，藤森 由夏，大石 真結，川口 甲介，守田 雅志，奥山 祐子，石井 直人，宗 孝紀
  • Organizer: 日本薬学会第141年会
• [Presentation] TNF 受容体の細胞内領域に含まれるTRAF 結合ペプチドモチーフの精密化を目指した研究 (2019)
  • Author(s): 飯田日向子，帯田孝之，宗孝紀，水口峰之
  • Organizer: 日本薬学会北陸支部第131回例会
• [Presentation] CD4陽性T細胞のIL-27受容体シグナルにおけるTRAF5の抑制性機能の解明 (2019)
  • Author(s): 河原永悟，藤森由夏，大石真結，川口甲介，守田雅志，奥山祐子，石井直人，宗孝紀
  • Organizer: 日本薬学会北陸支部第131回例会
• [Presentation] サイトカイン受容体 gp130 と TRAF タンパク質の相互作用様式の解明 (2019)
  • Author(s): 藤森由夏，河原永悟，川口甲介，守田雅志，帯田孝之，奥山祐子，水口峰之，石井直人，宗孝紀
  • Organizer: 日本薬学会北陸支部第131回例会
• [Presentation] TNFR-associated factor (TRAF) 5 expressed by intestinal epithelial cells promotes NF-kB-mediated inflammation via controlling TRAF2 stability in dextran sulfate sodium-induced colitis (2019)
  • Author(s): Phung HT, Nagashima H, Kobayashi S, Machiyama T, Sakurai T, Tayama S, Asao A, Okuyama Y, Ishii N, So T
  • Organizer: 第48回日本免疫学会学術集会
• [Presentation] IQGAP1 regulates ILC2 apoptosis in the lung (2019)
  • Author(s): Tayama S, Okuyama Y, Phung HT, Kawabe T, So T, Ishii N
  • Organizer: 第48回日本免疫学会学術集会
• [Presentation] Understanding the role of TRAF family proteins in gp130 signaling (2019)
  • Author(s): Fujimori Y, Kawahara E, Morita M, Okuyama Y, Ishii N, So T
  • Organizer: 第48回日本免疫学会学術集会
• [Presentation] TNF receptor-associated factor 5 inhibits IL-27 receptor signaling in CD4+ T-lymphocytes (2019)
  • Author(s): Kawahara E, Fujimori Y, Oishi M, Morita M, Ishii N, Okuyama Y, So T
  • Organizer: 第48回日本免疫学会学術集会
• [Presentation] GITR signaling negatively controls DSS-induced intestinal inflammation by regulating NK cells function (2019)
  • Author(s): Sakurai T, Okuyama Y, Hai Phung HT, So T, Nio M, Ishii N
  • Organizer: 第48回日本免疫学会学術集会
• [Presentation] GITR co-signaling controls group 2 innate lymphoid cells through IL-9 induction in allergic lung inflammation. (2018)
  • Author(s): Okuyama Y, Nagashima H, Motomura Y, Moro K, Sakurai T, Ndhlovu LC, Riccardi C, So T, Ishii N.
  • Organizer: 第47回日本免疫学会学術集会
• [Presentation] Functional regulation of plasmacytoid dendritic cells by TNF receptor associated factor 5. (2018)
  • Author(s): Kobayashi S, Sakurai T, Asao A, Phung HT, So T, Ishii N.
  • Organizer: 第47回日本免疫学会学術集会
• [Presentation] TNF receptor associated factor 5 controls oncostatin M-mediated lung inflammation. (2018)
  • Author(s): Machiyama T, So T, Harigae H, Ishii N.
  • Organizer: 第47回日本免疫学会学術集会
• [Presentation] TRAF5 maintains the expression level of TRAF2 in nonhematopoietic cells and exacerbates DSS-colitis in mice. (2018)
  • Author(s): Phung HT, Nagashima H, Kobayashi S, Machiyama T, Asao A, Okuyama Y, Ishii N, So T.
  • Organizer: 第47回日本免疫学会学術集会
• [Book] Co-signal Molecules in T Cell Activation (2019)
  • Author(s): So Takanori、Ishii Naoto
  • Total Pages: 32
  • Publisher: Springer
  • ISBN: 9789813297166