Analyses for expression and function of the sulfotransferase SULT2B1b

• Project/Area Number: 19H00983
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Medium-sized Section 43:Biology at molecular to cellular levels, and related fields
• Research Institution: Kyushu University
• Principal Investigator: Fukui Yoshinori 九州大学, 生体防御医学研究所, 教授 (60243961)
• Co-Investigator(Kenkyū-buntansha): 宇留野 武人 九州大学, 生体防御医学研究所, 准教授 (80532093)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥44,590,000 (Direct Cost: ¥34,300,000、Indirect Cost: ¥10,290,000); Fiscal Year 2021: ¥19,370,000 (Direct Cost: ¥14,900,000、Indirect Cost: ¥4,470,000); Fiscal Year 2020: ¥19,370,000 (Direct Cost: ¥14,900,000、Indirect Cost: ¥4,470,000); Fiscal Year 2019: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
• Keywords: 遺伝子発現 / 生理活性脂質 / 生体機能 / 酵素 / 生理活性資質

Outline of Research at the Start

研究代表者は、SULT2B1bによって生成されるコレステロール硫酸（CS）が、免疫細胞の遊走や活性化に重要なRac活性化因子であるDOCK2の触媒ドメインに会合し、その機能を阻害することを見出した。本研究では、SULT2B1bの遺伝子発現制御機構を解明し、その発現を個体レベルでモニターできるレポーターマウスを開発すると共に、妊娠時の胎盤や子宮、がん組織等を対象に、SULT2B1bを介したCS産生の免疫回避における機能的重要性を実証する。

Outline of Final Research Achievements

DOCK2 is a Rac activator critical for migration and activation of lymphocytes and its mutations cause severe immunodeficiency in humans. We recently found that cholesterol sulfate (CS), a lipid product of the sulfotransferase SULT2B1b, acts as a DOCK2 inhibitor and prevents tissue infiltration by effector T cells. In this study, we analyzed expression and function of CS, mainly focusing on cancer tissues and obtained the following results. 1) CS is abundantly produced in certain types of human cancers such as colon cancers. 2) CS-producing cancer cells exhibited resistance to cancer-specific T cell transfer and immune checkpoint blockade. Then, we screened chemical library and identified candidate compounds of SULT2B1b inhibitors.

Academic Significance and Societal Importance of the Research Achievements

本研究の成果は、新しいがんの免疫回避メカニズムの理解につながるものであり、その学術的意義は大きい。また現在、免疫チェックポイント阻害やCAR-T細胞療法に加え、iPS細胞を用いてがん特異的T細胞を増幅・移入する試みもなされているが、こららの免疫療法が効果を発揮するには、T細胞ががん組織に浸潤することが必要である。本研究の成果により、臨床応用可能なSULT2B1b阻害剤が開発され、がんの免疫回避環境を破壊することができれば、その社会的、経済的インパクトは大きいと期待される。

Research Products

• [Journal Article] Cancer-derived cholesterol sulfate is a key mediator to prevent tumor infiltration by effector T cells (2022)
  • Author(s): Tatsuguchi T., Uruno T., Sugiura Y., Sakata D., Izumi Y., Sakurai T., Hattori Y., Oki E., Kubota N., Nishimoto K., Oyama M., Kunimura K., Ohki T., Bamba T., Tahara H., Sakamoto M., Nakamura M., Suematsu M., Fukui Y.
  • Journal Title: Int. Immunol. Volume: － Issue: 5 Pages: 277-289
  • DOI: 10.1093/intimm/dxac002
  • Peer Reviewed / Open Access
• [Journal Article] Pharmacological intervention of cholesterol sulfate-mediated T cell exclusion promotes antitumor immunity (2022)
  • Author(s): Takaaki Tatsuguchi, Takehito Uruno, Yuki Sugiura, Kounosuke Oisaki, Daisuke Takaya, Daiji Sakata, Yoshihiro Izumi, Takaya Togo, Yuko Hattori, Kazufumi Kunimura, Testuya Sakurai, Teruki Honma, Takeshi Bamba, Masafumi Nakamura, Motomu Kanai, Makoto Suematsu, Yoshinori Fukui
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: -
  • Peer Reviewed / Open Access
• [Journal Article] Targeted inhibition of EPAS1-driven IL-31 production by a small-molecule compound. (2021)
  • Author(s): Kamikaseda Y, Uruno T, Kunimura K, Harada A, Saiki K, Oisaki K, Sakata D, Nakahara T, Kido-Nakahara M, Kanai M, Nakamura S, Ohkawa Y, Furue M, Fukui Y.
  • Journal Title: J Allergy Clin Immunol. Volume: 148 Issue: 2 Pages: 633-638
  • DOI: 10.1016/j.jaci.2021.03.029
  • Peer Reviewed / Open Access
• [Journal Article] 2.論文標題 DOCK8 deficiency causes a skewing to type 2 immunity in the gut with expansion of group 2 innate lymphoid cells. (2021)
  • Author(s): Matsubara K, Kunimura K, Yamane N, Aihara R, Sakurai T, Sakata D, Uruno T, Fukui Y
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 559 Pages: 135-140
  • DOI: 10.1016/j.bbrc.2021.04.094
  • Peer Reviewed / Open Access
• [Journal Article] A conserved PI(4,5)P2-binding domain is critical for immune regulatory function of DOCK8 (2021)
  • Author(s): Sakurai Tetsuya、Kukimoto-Niino Mutsuko、Kunimura Kazufumi、Yamane Nana、Sakata Daiji、Aihara Ryosuke、Yasuda Tomoharu、Yokoyama Shigeyuki、Shirouzu Mikako、Fukui Yoshinori、Uruno Takehito
  • Journal Title: Life Science Alliance Volume: 4 Issue: 4 Pages: e202000873-e202000873
  • DOI: 10.26508/lsa.202000873
  • Peer Reviewed / Open Access
• [Journal Article] DOCK8 controls survival of group 3 innate lymphoid cells in the gut through Cdc42 activation. (2021)
  • Author(s): Aihara R, Kunimura K, Watanabe M, Uruno T, Yamane N, Sakurai T, Sakata D, Nishimura F, Fukui Y
  • Journal Title: International Immunology Volume: 33 Issue: 3 Pages: 149-160
  • DOI: 10.1093/intimm/dxaa066
  • NAID: 120007166274
  • Peer Reviewed
• [Journal Article] Expression of leukotriene B4 receptor 1 defines functionally distinct DCs that control allergic skin inflammation. (2020)
  • Author(s): Tomoaki Koga, Fumiyuki Sasaki, Kazuko Saeki, Soken Tsuchiya, Toshiaki Okuno, Mai Ohba, Takako Ichiki, Satoshi Iwamoto, Hirotsugu Uzawa, Keiko Kitajima, Chikara Meno, Eri Nakamura, Norihiro Tada, Yoshinori Fukui, Junichi Kikuta, Masaru Ishii, Yukihiko Sugimoto, and Mitsuyoshi Nakao, Takehiko Yokomizo.
  • Journal Title: Cellular & Molecular Immunology Volume: 8 Issue: 6 Pages: 1-13
  • DOI: 10.1038/s41423-020-00559-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cul5-type Ubiquitin Ligase KLHDC1 Contributes to the Elimination of Truncated SELENOS Produced by Failed UGA/Sec Decoding (2020)
  • Author(s): Okumura Fumihiko、Fujiki Yuha、Oki Nodoka、Osaki Kana、Nishikimi Akihiko、Fukui Yoshinori、Nakatsukasa Kunio、Kamura Takumi
  • Journal Title: iScience Volume: 23 Issue: 3 Pages: 100970-100970
  • DOI: 10.1016/j.isci.2020.100970
  • Peer Reviewed / Open Access
• [Journal Article] Selective role of neurokinin B in IL-31-induced itch response in mice (2019)
  • Author(s): Sakata Daiji、Uruno Takehito、Matsubara Keisuke、Andoh Tsugunobu、Yamamura Kazuhiko、Magoshi Yuki、Kunimura Kazufumi、Kamikaseda Yasuhisa、Furue Masutaka、Fukui Yoshinori
  • Journal Title: Journal of Allergy and Clinical Immunology Volume: 144 Issue: 4 Pages: 1130-1133
  • DOI: 10.1016/j.jaci.2019.06.031
  • Peer Reviewed / Open Access
• [Journal Article] S100A4 Protein Is Essential for the Development of Mature Microfold Cells in Peyer’s Patches (2019)
  • Author(s): Kunimura K, Sakata D, Tun X, Uruno T, Ushijima M, Katakai T, Shiraishi A, Aihara R, Kamikaseda Y, Matsubara K, Kanegane H, Sawa S, Eberl G, Ohga S, Yoshikai Y, Fukui Y.
  • Journal Title: Cell Reports Volume: 29 Issue: 9 Pages: 2823-2834
  • DOI: 10.1016/j.celrep.2019.10.091
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] DOCK family proteins: key players in immune surveillance mechanisms (2019)
  • Author(s): Kunimura Kazufumi、Uruno Takehito、Fukui Yoshinori
  • Journal Title: International Immunology Volume: 32 Issue: 1 Pages: 5-15
  • DOI: 10.1093/intimm/dxz067
  • Peer Reviewed / Open Access
• [Presentation] IL-31産生の分子基盤の解明とその創薬研究への展開 (2022)
  • Author(s): 福井 宣規
  • Organizer: 日本薬理学会
  • Invited
• [Presentation] IL-31の産生と痒み伝達の分子基盤: 基礎生物学から創薬研究へ (2021)
  • Author(s): 福井 宣規
  • Organizer: 国際痒み学会
  • Int'l Joint Research / Invited
• [Presentation] IL-31の産生と痒み伝達の分子基盤 (2020)
  • Author(s): 福井宣規、坂田大治、中原剛士、古江増隆
  • Organizer: 第50回日本皮膚免疫アレルギー学会総会学術大会
  • Invited
• [Presentation] The transcription factor EPAS1 links DOCK8 deficiency to atopic skin inflammation via IL-31 induction (2019)
  • Author(s): Kunimura K, Yamamura K, Fukui Y
  • Organizer: American Association of Immunologist Annual Meeting
  • Int'l Joint Research
• [Presentation] The biological function of naturally occurring DOCK2 inhibitor in tissue-specific immune evasion (2019)
  • Author(s): Sakurai T, Uruno T, Fukui Y
  • Organizer: American Association of Immunologist Annual Meeting
  • Int'l Joint Research
• [Presentation] Role of Jmjd6 in Aire expression and self-tolerance induction in the thymus (2019)
  • Author(s): Matsubara K, Yanagihara T, Fukui Y
  • Organizer: American Association of Immunologist Annual Meeting
  • Int'l Joint Research
• [Presentation] Identification of the molecule required for transmission of IL-31-induced itch sensation in the spinal cord (2019)
  • Author(s): Sakata D, Fukui Y
  • Organizer: 第48回日本免疫学会学術集会
• [Presentation] IL-31による痒み伝達の分子基盤 (2019)
  • Author(s): 福井宣規
  • Organizer: 環境医学研究所・順天堂かゆみ研究センター第５回学術シンポジウム
  • Invited
• [Patent(Industrial Property Rights)] SULT2B1b阻害剤、CS生成阻害剤、及び抗がん免疫増強作用を有する医薬組成物 (2021)
  • Inventor(s): 福井宣規 他
  • Industrial Property Rights Holder: 九州大学、東京大学、慶應大学、理研
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2021-173456
  • Filing Date: 2021