Alteration of Biological Responses by Different Qualities of Self-Recognition Receptors

• Project Area: Reevaluation of self recognition by immune system to decipher its physiological advantages and pathological risk
• Project/Area Number: 23H04773
• Research Category: Grant-in-Aid for Transformative Research Areas (A)
• Allocation Type: Single-year Grants
• Review Section: Transformative Research Areas, Section (III)
• Research Institution: Institute of Science Tokyo
• Principal Investigator: 清水 重臣 東京科学大学, 総合研究院, 特任教授 (70271020)
• Project Period (FY): 2023-04-01 – 2025-03-31
• Project Status: Completed (Fiscal Year 2024)
• Budget Amount: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000); Fiscal Year 2024: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2023: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000)
• Keywords: GOMED / 受容体 / 糖鎖 / リガンド

Outline of Research at the Start

自己認識が「功」となる場合や「罪」となる場合があることは明らかであり、本研究では、受容体の面から、自己認識機構の功罪を明らかにする。具体的には、受容体の発現状態によって、細胞応答はどのように変化するのか？　受容体の発現状態は、タンパク質分解機構GOMEDによって如何に適切に制御されているか？GOMEDを欠損したマウスでは、いかなる受容体が、どのように関与しているのか？ を明らかにする。

Outline of Annual Research Achievements

自己由来の炎症誘導因子(DAMPs)は、免疫細胞の細胞表面に発現するセンサーによって認識され、さまざまな生体応答を引き起こす。この時、
自己抗原等に反応する生体応答は、自己防衛に必要な生体応答ばかりではなく、行き過ぎた生体応答が誘導されることもある。この様な自己反応の功罪は、DAMPsが関与するだけでなく、受容体の量や質によっても影響される。本研究では、自己反応の功罪の決定に受容体の量や質が如何に重要であるかを明らかにするとともに、その発現制御機構を明らかにする。具体的には、(1)受容体の量や質は、タンパク質分解機構GOMEDなどによって制御されているが、その実態は如何なるものであるか？(2)受容体の異常による疾患の病態にGOMEDは如何に関わっているのか？を明らかにする。
今年度は、GOMED活性化の有無による受容体の発現状態の違いを解析し、GOMEDの活性化によって発現量が減ること、逆にGOMEDの抑制により、発現量が上昇することを見出した。また、GOMED欠損細胞では、この受容体発現が更新することを見出した。
さらに、TRAPSの遺伝子変異を模倣した疾患モデルマウスを作製し、その表現系を解析した。

Research Progress Status

令和6年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

令和6年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Novel cell-to-cell communications between macrophages and fibroblasts regulate obesity-induced adipose tissue fibrosis (2025)
  • Author(s): Kohda H,Tanaka M,Shichino S、Arakawa S、Komori T、Ito A、Wada E、Ochi K、Yuan X、Takeda T、Saiki A、Tatsuno I、Ikeda K、Miyai Y、Enomoto A、Morikawa Y、Shimizu S、Ueha S、Matsushima K、Ogawa Y、Suganami T
  • Journal Title: Diabetes Volume: 10 Issue: 7 Pages: 1-1
  • DOI: 10.2337/db24-0762
  • Peer Reviewed / Open Access
• [Journal Article] Alternative autophagy dampens UVB-induced NLRP3 inflammasome activation in human keratinocytes (2024)
  • Author(s): Hasegawa Tatsuya、Noguchi Saori、Nakashima Masaya、Miyai Masashi、Goto Makiko、Matsumoto Yuko、Torii Satoru、Honda Shinya、Shimizu Shigeomi
  • Journal Title: Journal of Biological Chemistry Volume: 300 Issue: 4 Pages: 107173-107173
  • DOI: 10.1016/j.jbc.2024.107173
  • Peer Reviewed / Open Access
• [Journal Article] <i>BCR::ABL1</i>‐induced mitochondrial morphological alterations as a potential clinical biomarker in chronic myeloid leukemia (2024)
  • Author(s): Suzuki Kohjin、Watanabe Naoki、Torii Satoru、Arakawa Satoko、Ochi Kiyosumi、Tsuchiya Shun、Yamada Kazuhiro、Kawamura Yoko、Ota Sadao、Komatsu Norio、Shimizu Shigeomi、Ando Miki、Takaku Tomoiku
  • Journal Title: Cancer Science Volume: 116 Issue: 3 Pages: 673-689
  • DOI: 10.1111/cas.16424
  • Peer Reviewed / Open Access
• [Journal Article] Presence of Gut Microbiota Worsens D‐Galactosamine and Lipopolysaccharide‐Induced Hepatic Injury in Mice (2024)
  • Author(s): Ohshima Kazuma、Torii Satoru、Shimizu Shigeomi
  • Journal Title: Genes to Cells Volume: 30 Issue: 1 Pages: 1-12
  • DOI: 10.1111/gtc.13183
  • Peer Reviewed
• [Journal Article] ULK1-regulated AMP sensing by AMPK and its application for the treatment of chronic kidney disease (2024)
  • Author(s): Yanagi T、Kikuchi H、Takeuchi K、Susa K、Mori T、Chiga M、Yamamoto K、Furukawa A、Kanazawa T、Kato Y、Takahashi N、Suzuki T、Mori Y、Carter B.、Mori M、Nakano Yu、Fujiki T、Hara Y、Suzuki S、Ando F、Mandai S、Honda S、Torii S、Shimizu S、Tanaka H、Fujii Y、Rai T、Uchida S、Sohara E
  • Journal Title: Kidney International Volume: 106 Issue: 5 Pages: 887-906
  • DOI: 10.1016/j.kint.2024.08.024
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Photo-protective role of ATG5/ATG7-independent alternative autophagy in human keratinocytes (2024)
  • Author(s): Hasegawa Tatsuya、Nakashima Masaya、Torii Satoru、Honda Shinya、Shimizu Shigeomi
  • Journal Title: Autophagy Reports Volume: 3 Issue: 1 Pages: 2396212-2396212
  • DOI: 10.1080/27694127.2024.2396212
  • Peer Reviewed
• [Journal Article] Subcellular localization and ER-mediated cytotoxic function of α1A and α1ACT in spinocerebellar ataxia type 6 (2024)
  • Author(s): Wang Di、Honda Shinya、Shin Min Kyoung、Watase Kei、Mizusawa Hidehiro、Ishikawa Kinya、Shimizu Shigeomi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 695 Pages: 149481-149481
  • DOI: 10.1016/j.bbrc.2024.149481
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Modeling of Retina and Optic Nerve Ischemia-Reperfusion Injury through Hypoxia-Reoxygenation in Human Induced Pluripotent Stem Cell-Derived Retinal Ganglion Cells. (2024)
  • Author(s): Yoshida T, Yokoi T, Tanaka T, Matsuzaka E, Saida Y, Nishina S, Takada S, Shimizu S, Azuma N
  • Journal Title: Cells Volume: 13 Issue: 2 Pages: 130-130
  • DOI: 10.3390/cells13020130
  • Peer Reviewed / Open Access
• [Journal Article] Identification of a novel type of focal adhesion remodelling via FAK/FRNK replacement, and its contribution to cancer progression (2023)
  • Author(s): Tsujioka M, Miyazawa K, Ohmuraya M, Nibe Y, Shirokawa T, Hayasaka H, Mizushima T, Fukuma T, Shimizu S
  • Journal Title: Cell Death & Disease Volume: 14 Issue: 4 Pages: 256-256
  • DOI: 10.1038/s41419-023-05774-4
  • Peer Reviewed / Open Access
• [Journal Article] Lactiplantibacillus plantarum OLL2712 Induces Autophagy via MYD88 and Strengthens Tight Junction Integrity to Promote the Barrier Function in Intestinal Epithelial Cells (2023)
  • Author(s): Watanabe-Yasuoka Yumiko、Gotou Ayako、Shimizu Shigeomi、Sashihara Toshihiro
  • Journal Title: Nutrients Volume: 15 Issue: 12 Pages: 2655-2655
  • DOI: 10.3390/nu15122655
  • Peer Reviewed / Open Access
• [Journal Article] Development of small fluorescent probes for the analysis of autophagy kinetics (2023)
  • Author(s): Sakurai Hajime Tajima、Iwashita Hidefumi、Arakawa Satoko、Yikelamu Alifu、Kusaba Mizuki、Kofuji Satoshi、Nishina Hiroshi、Ishiyama Munetaka、Ueno Yuichiro、Shimizu Shigeomi
  • Journal Title: iScience Volume: 26 Issue: 7 Pages: 107218-107218
  • DOI: 10.1016/j.isci.2023.107218
  • Peer Reviewed / Open Access
• [Journal Article] Biogenesis of fibrils requires <i>C</i>‐mannosylation of <scp>PMEL</scp> (2023)
  • Author(s): Kawahara Ryota、Usami Tomoko、Arakawa Satoko、Kamo Hiroki、Suzuki Takehiro、Komatsu Ryosuke、Hara Hiroyuki、Niwa Yuki、Shimizu Erina、Dohmae Naoshi、Shimizu Shigeomi、Simizu Siro
  • Journal Title: The FEBS Journal Volume: 290 Issue: 22 Pages: 5373-5394
  • DOI: 10.1111/febs.16927
  • Peer Reviewed
• [Journal Article] Involvement of casein kinase 1 epsilon/delta (Csnk1e/d) in the pathogenesis of familial Parkinson's disease caused by <scp>CHCHD2</scp> (2023)
  • Author(s): Torii Satoru、Arakawa Satoko、Sato Shigeto、Ishikawa Kei‐ichi、Taniguchi Daisuke、Sakurai Hajime Tajima、Honda Shinya、Hiraoka Yuuichi、Ono Masaya、Akamatsu Wado、Hattori Nobutaka、Shimizu Shigeomi
  • Journal Title: EMBO Molecular Medicine Volume: 15 Issue: 9
  • DOI: 10.15252/emmm.202317451
  • Peer Reviewed / Open Access
• [Journal Article] Beclin1 is essential for the pancreas development (2023)
  • Author(s): Mehanna Sally、Arakawa Satoko、Imasaka Mai、Chen Wenting、Nakanishi Yuto、Nishiura Hiroshi、Shimizu Shigeomi、Ohmuraya Masaki
  • Journal Title: Developmental Biology Volume: 504 Pages: 113-119
  • DOI: 10.1016/j.ydbio.2023.09.008
  • Peer Reviewed / Open Access
• [Journal Article] Identification of small compounds that inhibit multiple myeloma proliferation by targeting c-Maf transcriptional activity (2023)
  • Author(s): Asano Kenichi、Kikuchi Kenta、Takehara Miki、Ogasawara Manami、Yoshioka Yuki、Ohnishi Kie、Iwata Ayaka、Shimizu Shigeomi、Tanaka Masato
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 684 Pages: 149135-149135
  • DOI: 10.1016/j.bbrc.2023.149135
  • Peer Reviewed / Open Access
• [Journal Article] Uncovering the Localization and Function of a Novel Read-Through Transcript ‘TOMM40-APOE’ (2023)
  • Author(s): Chang Shichen、Torii Satoru、Inamo Jun、Ishikawa Kinya、Kochi Yuta、Shimizu Shigeomi
  • Journal Title: Cells Volume: 13 Issue: 1 Pages: 69-69
  • DOI: 10.3390/cells13010069
  • Peer Reviewed / Open Access
• [Presentation] Autophagy regulates centrosome number by degrade cytosolic Cep63 and inhibits tumorigenesis (2025)
  • Author(s): 本田真也、清水重臣
  • Organizer: 第４回Cell Deathコロキアム
  • Invited
• [Presentation] ゴルジ体におけるタンパク質分解機構GOMEDの解析 (2024)
  • Author(s): 清水重臣
  • Organizer: 第76回細胞生物学会
• [Remarks] 病態細胞生物ホームページ
  • URL: https://www.tmd.ac.jp/mri/pcb/index.html