Analysis of immunoproteasome function in immune cell development

• Project/Area Number: 21K06956
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49030:Experimental pathology-related
• Research Institution: Okayama University of Science
• Principal Investigator: Hemmi Hiroaki 岡山理科大学, 獣医学部, 教授 (20451924)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2023: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: プロテアソーム / 免疫担当細胞分化 / モデルマウス / 免疫プロテアソーム / 遺伝子バリアント / 細胞分化 / 遺伝子改変マウス / 遺伝子変異 / 免疫細胞分化 / 造血

Outline of Research at the Start

細胞内の不要/不良なタンパク質の分解や、細胞内シグナル伝達、抗原提示などにも関与する巨大なタンパク複合体であるプロテアソームの機能低下や機能異常により、慢性の難治性炎症を特徴とするプロテアソーム関連自己炎症性症候群が発症することが明らかにされてきている。本計画では、ヒト患者にて見いだされたプロテアソームサブユニットの遺伝子変異を導入したノックインマウスの解析を通して、プロテアソームの新規の機能的意義の解明を目指す。

Outline of Final Research Achievements

The proteasome is a large protein complex degrading intracellular protein, and plays important roles in maintenance of cellular homeostasis including intracellular signal transduction and processing of antigen peptides. Genetic variation(s) in proteasome subunit genes might lead to severe autoinflammatory diseases, called proteasome-associated autoinflammatory syndrome (PRAAS). In this study, we analyzed mutant mice carrying a genetic variant in a proteasome subunit gene identified in PRAAS-like patients. We found that heterozygous mutant mice showed reduced lymphocytes and increased myeloid cells. In homozygous mice, lymphocytes and dendritic cells were hardly detected, and lymphoid biased multipotent progenitors were also affected. These results suggest that proteasome function is important for immune cell development. Thus, this model mouse is useful to analyzing pathological and physiological function of proteasome in hematopoiesis as well as its pathological functions in PRAAS.

Academic Significance and Societal Importance of the Research Achievements

プロテアソームは、様々な細胞や組織における恒常性の維持などに関与しており、その異常は炎症性疾患やがんなど多様な疾患でも報告されている。そのため、プロテアソームサブユニット遺伝子に生じたバリアントにより発症するプロテアソーム関連自己炎症候群について、その病態や分子基盤を解明することは、当該疾患だけでなく多様な疾患の治療法の開発にも有用であると考えられる。本研究では、当該疾患患者由来の遺伝子バリアントを導入したマウスを解析した。本モデルマウスの解析により、プロテアソームの生理的機能の解明に加え、炎症病態等の新たなメカニズムや新規の炎症病態制御剤の開発につながる成果が得られることが期待される。

Research Products

• [Journal Article] TLR7/8 stress response drives histiocytosis in SLC29A3 disorders (2023)
  • Author(s): Shibata Takuma、Sato Ryota、Taoka Masato、Saitoh Shin-Ichiroh、Komine Mayumi、（他16人）、Ohto Umeharu、Shimizu Toshiyuki、Ozawa Manabu、Yoshida Nobuaki、Isobe Toshiaki、Latz Eicke、Mukai Kojiro、Taguchi Tomohiko、Hemmi Hiroaki、Akira Shizuo、Miyake Kensuke
  • Journal Title: Journal of Experimental Medicine Volume: 220 Issue: 9 Pages: 320230054-320230054
  • DOI: 10.1084/jem.20230054
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Tmem45b is essential for inflammation- and tissue injury?induced mechanical pain hypersensitivity (2022)
  • Author(s): Tanioku Tadashi、Nishibata Masayuki、Tokinaga Yasuyuki、Konno Kohtaro、Watanabe Masahiko、Hemmi Hiroaki、Fukuda-Ohta Yuri、Kaisho Tsuneyasu、Furue Hidemasa、Kawamata Tomoyuki
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 119 Issue: 45 Pages: 119-119
  • DOI: 10.1073/pnas.2121989119
  • Peer Reviewed / Open Access
• [Journal Article] Expression profile of immunoregulatory factors in canine tumors (2022)
  • Author(s): Murakami Kohei、Miyatake Saki、Miyamae Jiro、Saeki Kanna、Shinya Mizutani、Akashi Natsuki、Mitsui Ikki、Kobayashi Kosuke、Saeki Kohei、Maeta Noritaka、Kanda Teppei、Okamura Yasuhiko、Hemmi Hiroaki
  • Journal Title: Veterinary Immunology and Immunopathology Volume: 253 Pages: 110505-110505
  • DOI: 10.1016/j.vetimm.2022.110505
  • Peer Reviewed
• [Journal Article] Augmentation of STING‐induced type I interferon production in COPA syndrome (2021)
  • Author(s): Kato Takashi、Yamamoto Masaki、Honda Yoshitaka、Orimo Takashi、Sasaki Izumi、Murakami Kohei、Hemmi Hiroaki、Fukuda‐Ohta Yuri、Isono Kyoichi、Takayama Saki、Nakamura Hidenori、Otsuki Yoshiro、Miyamoto Toshiaki、Takita Junko、Yasumi Takahiro、Nishikomori Ryuta、Matsubayashi Tadashi、Izawa Kazushi、Kaisho Tsuneyasu
  • Journal Title: Arthritis & Rheumatology Volume: in press Issue: 11 Pages: 2105-2115
  • DOI: 10.1002/art.41790
  • Peer Reviewed / Open Access
• [Journal Article] Radiation inducible MafB gene is required for thymic regeneration (2021)
  • Author(s): Daiki Hashimoto, Jose Gabriel R. Colet, Aki Murashima, Kota Fujimoto, Yuko Ueda, Kentaro Suzuki, Taiju Hyuga, Hiroaki Hemmi, Tsuneyasu Kaisho, Satoru Takahashi, Yousuke Takahama and Gen Yamada1
  • Journal Title: Scientific Reports Volume: - Issue: 1 Pages: 10439-10439
  • DOI: 10.1038/s41598-021-89836-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Heterozygous missense variant of the proteasome subunit β-type 9 causes neonatal-onset autoinflammation and immunodeficiency (2021)
  • Author(s): Kanazawa N, Hemmi H, Kinjo N, Ohnishi H, Hamazaki J, M.H, K.A, M.T, H.S, K.N, K.S, H.Y, I.K, N.R, T.M, Y.Y, T.S, O.T, O.T, K.T, S.I, F.Y, W.N, I.Y, K.K, O.S, T.T, N.K, M.S, Y.K, Kaisho T
  • Journal Title: Nature Communications Volume: 12 Issue: 1 Pages: 0-0
  • DOI: 10.1038/s41467-021-27085-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Impairment of plasma cell generation in mice carrying a proteasome subunit β1i missense mutation derived from patients with autoinflammation and adaptive immune deficiency (2023)
  • Author(s): Takashi Kato, Asumi Yamamoto, Izumi Sasaki, Naoko Wakaki-Nishiyama, Hiroaki Hemmi, Nobuo Kanazawa, Wataru Ise and Tsuneyasu Kaisho
  • Organizer: JAM on Cell Death, 2023
  • Int'l Joint Research
• [Presentation] Impaired plasma cell differentiation in a novel model mouse of the proteasome-associated autoinflammatory syndromes with immunodeficiency. (2023)
  • Author(s): Takashi Kato, Asumi Yamamoto, Izumi Sasaki, Naoko Wakaki-Nishiyama, Hiroaki Hemmi, Nobuo Kanazawa, Wataru Ise, Tsuneyasu Kaisho.
  • Organizer: The 29th International Symposium on Molecular Cell Biology of Macrophages. (ISICR/MMCB2023 Joint Symposium)
• [Presentation] 免疫不全を伴うプロテアソーム関連自己炎症症候群モデルマウスの解析 (2022)
  • Author(s): 邊見弘明
  • Organizer: 第20回 四国免疫フォーラム
• [Presentation] Dendritic cells and T cell abnormalities in a novel mouse model of COPA syndrome (2022)
  • Author(s): Takashi Kato, Asumi Yamamoto, Izumi Sasaki, Naoko Wakaki-Nishiyama, Kohei Murakami, Hiroaki Hemmi, Yoshitaka Honda, Kazushi Izawa, Ryuta Nishikomori, Tsuneyasu Kaisho
  • Organizer: JSICR/MMCB 2022 Joint Symposium
  • Int'l Joint Research
• [Presentation] Activation of type I Interferon signaling in dendritic cells and T cells of the mouse model of COPA syndrome (2022)
  • Author(s): Takashi Kato, Ryota Yamasaki, Naoko Wakaki Nishiyama, Izumi Sasaki, Shiori Kaji, Kohei Murakami, Hiroaki Hemmi, Yoshitaka Honda, Kazushi Izawa, Yoshiro Otsuki, Tadashi Matsubayashi, Ryuta Nishikomori, Tsuneyasu Kaisho
  • Organizer: 日本免疫毒性学会 第29回学術年会
• [Presentation] 和歌山からの研究発信 ―自己炎症性疾患― (2022)
  • Author(s): 改正恒康, 金澤伸雄, 邊見弘明, 佐々木泉, 加藤喬, 山本明日美
  • Organizer: 第90回 和歌山医学会
• [Presentation] COPA症候群の新規モデルマウスにおけるSTINGの活性化とT細胞の異常 (2022)
  • Author(s): 加藤喬、折茂貴是、大田（福田）有里、西山奈央子、中井千尋、佐々木泉、村上康平、邊見弘明、本田吉孝、井澤和司、八角高裕、大月寛郎、松林正、西小森隆太、改正恒康
  • Organizer: 第5回日本免疫不全・自己炎症学会学術集会
• [Presentation] Impaired monocyte and dendritic cell development in mice carrying a mutation identified from the proteasome-associated autoinflammation and immunodeficiency disease patient (2021)
  • Author(s): Hiroaki Hemmi, Takashi Orimo, Naoko Nishiyama, Takashi Kato, Toshiya Ozasa, Izumi Sasaki, Hidenori Ohnishi, Noriko Kinjo, Nobuo Kanazawa, Tsuneyasu Kaisho
  • Organizer: The 27th International Symposium on Molecular Cell Biology of Macrophages
  • Int'l Joint Research
• [Presentation] Augmented STING signaling in a new mouse model of COPA syndrome. The 27th International Symposium on Molecular Cell Biology of Macrophages (2021)
  • Author(s): Takashi Kato, Takashi Orimo, Yuri Fukuda-Ohta, Naoko Nishiyama, Izumi Sasaki, Hiroaki Hemmi, Yoshitaka Honda, Kazushi Izawa, Ryuta Nishikomori, Tsuneyasu Kaisho
  • Organizer: The 27th International Symposium on Molecular Cell Biology of Macrophages
  • Int'l Joint Research
• [Presentation] The role of IRE1α in cholera toxin B-induced interleukine-1β production from resident peritoneal macrophages. The 27th International Symposium on Molecular Cell Biology of Macrophages (2021)
  • Author(s): Izumi Sasaki, Chihiro Nakai, Shuhei Morita, Daisuke Okuzaki, Yuri Fukuda-Ohta, Takashi Orimo, Hiroaki Hemmi, Koichi Furukawa, Tsuneyasu Kaisho
  • Organizer: The 27th International Symposium on Molecular Cell Biology of Macrophages
  • Int'l Joint Research
• [Presentation] Chemokine-medicated delivery of cancer peptide vaccine to a dendritic cell subset with high crosspresentation activity (2021)
  • Author(s): Yuki Mizumoto, Hiroaki Hemmi, Masahiro Katsuda, Yuri Fukuda-Ohta, Takashi Orimo, Izumi Sasaki, Koji Tamada, Hiroki Yamaue, Tsuneyasu Kaisho
  • Organizer: The 27th International Symposium on Molecular Cell Biology of Macrophages
  • Int'l Joint Research
• [Presentation] Interstitial Lung Disease and abnormal STING activation in COPA V242G heterozygous variant mice (2021)
  • Author(s): Takashi Kato, Takashi Orimo, Yuri Fukuda-Ohta, Naoko Wakaki-Nishiyama, Chihiro Nakai, Izumi Sasaki, Kohei Murakami, Hiroaki Hemmi, Yoshitaka Honda, Kazushi Izawa, Yoshiro Otsuki, Tadashi Matsubayashi, Ryuta Nishikomori, Tsuneyasu Kaisho
  • Organizer: 16th Meeting of the International Endotoxin and Innate Immunity Society
  • Int'l Joint Research
• [Presentation] Analysis of innate immune cells in proteasome subunit mutant mice (2021)
  • Author(s): Hiroaki Hemmi, Takashi Orimo, Izumi Sasaki, Takashi Kato, Yuri Fukuda-Ohta, Noriko Kinjo, Hidenori Ohnishi, Nobuo Kanazawa, Tsuneyasu Kaisho
  • Organizer: 16th Meeting of the International Endotoxin and Innate Immunity Society
  • Int'l Joint Research
• [Presentation] Impaired development of myeloid cells in proteasome subunit mutant mice (2021)
  • Author(s): Hiroaki Hemmi, Takashi Orimo, Izumi Sasaki, Takashi Kato, Yuri Fukuda-Ohta, Noriko Kinjo, Hidenori Ohnishi, Nobuo Kanazawa, Tsuneyasu Kaisho
  • Organizer: 第50回日本免疫学会学術集会
• [Presentation] Unique location in the immunoproteasome complex of a variant causing proteasome-associated autoinflammatory syndrome with immunodeficiency (2021)
  • Author(s): Nobuo Kanazawa, Hiroaki Hemmi, Noriko Kinjo, Hidenori Ohnishi, Jun Hamazaki, Hiroyuki Mishima, Akira Kinoshita, Tsunehiro Mizushima, Shigeo Murata, Koh-ichiro, Yoshiura, Tsuneyasu Kaisho
  • Organizer: 第50回日本免疫学会学術集会
• [Presentation] Hyperactivation of STING-induced type I interferon pathway in dendritic cells from novel mice model for an autoinflammatory disease, COPA syndrome (2021)
  • Author(s): Takashi Kato, Takashi Orimo, Yuri Fukuda-Ohta, Sasaki Izumi. Hiroaki Hemmi, Yoshitaka Honda, Kazushi Izawa, Ryuta Nishikomori, Tsuneyasu Kaisho
  • Organizer: 第50回日本免疫学会学術集会
• [Presentation] Sublingual dendritic cell (DC) - T cell clusters and distribution of DCs in the oral cavity (2021)
  • Author(s): Yutaka Kusumoto, Tsuneyasu Kaisho, Hiroaki Hemmi, Tomoya Katakai, Tetsuya Honda, Junichi Kikuta, Kousuke Kataoka, Taiki Moriya, Masaru Ishii, Kenji Kabashima, Michio Tomura
  • Organizer: 第50回日本免疫学会学術集会
• [Presentation] Hypomorphic mutation of Lig4 gene in mice predisposes to intestinal inflammation driven by CD4+ Th1 cells (2021)
  • Author(s): Yusuke Yamashita, Takashi Orimo, Takashi Kato, Yuri Fukuda-Ohta, Izumi Sasaki, Hiroaki Hemmi, Shinobu Tamura, Tsuneyasu Kaisho
  • Organizer: 第50回日本免疫学会学術集会
• [Presentation] 自己炎症性疾患COPA症候群変異マウスにおけるSTINGシグナルの活性化 (2021)
  • Author(s): 加藤喬、折茂貴是、大田（福田）有里、西山奈央子、中井千尋、張江伊水、田中日向子、佐々木泉、村上康平、邊見弘明、本田吉孝、井澤和司、西小森隆太、改正恒康
  • Organizer: 第85回日本インターフェロン・サイトカイン学会学術集会
• [Presentation] Molecular mechanisms of type I interferonopathy in a novel COPA syndrome model mouse (2021)
  • Author(s): Takashi Kato, Takashi Orimo, Yuri Fukuda-Ohta, Naoko Wakaki-Nishiyama, Chihiro Nakai, Izumi Sasaki, Kohei Murakami, Hiroaki Hemmi, Yoshitaka Honda, Kazushi Izawa, Yoshiro Otsuki, Tadashi Matsubayashi, Ryuta Nishikomori, Tsuneyasu Kaisho
  • Organizer: 第28回日本免疫毒性学会学術集会
• [Presentation] 樹状細胞サブセット(XCR1+DC) への特異的送達によるがんペプチドワクチン療法 (2021)
  • Author(s): 水本有紀、勝田将裕、宮澤基樹、北畑裕司、宮本篤、中森幹人、松田健司、尾島敏康、邊見弘明、玉田耕治、改正恒康、山上裕機
  • Organizer: 第25回日本がん免疫学会総会
• [Presentation] XCR1 陽性樹状細胞分化におけるプロテアソームの役割 (2021)
  • Author(s): 西山奈央子、佐々木泉、邊見弘明、改正恒康
  • Organizer: 第25回日本がん免疫学会総会
• [Presentation] XCR1+ DC をターゲットにしたwhole-cell-vaccine の開発 (2021)
  • Author(s): 宮本篤、勝田将裕、宮澤基樹、北畑裕司、水本有紀、小林良平、尾島敏康、邊見弘明、戸村道夫、改正恒康、山上裕機
  • Organizer: 第25回日本がん免疫学会総会