Elucidating the regulatory mechanisms and physiological functions of immunomodulation by the Hippo intracellular signaling pathway

• Project/Area Number: 18H02438
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 44010:Cell biology-related
• Research Institution: Kumamoto University
• Principal Investigator: Moroishi Toshiro 熊本大学, 大学院生命科学研究部(医), 教授 (30647722)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000); Fiscal Year 2020: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2019: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2018: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000)
• Keywords: Hippoシグナル / 免疫応答 / 免疫原性 / 自己免疫疾患 / Hippo経路 / 免疫

Outline of Final Research Achievements

The immune system plays a pivotal role in preventing illness by recognizing and eliminating abnormal pathogens and cancer cells. However, the mechanism by which cells induce an immune response is not fully understood. In this research project, we focused on the Hippo intracellular signaling pathway to elucidate the mechanisms by which this pathway controls the immune response, aiming to develop therapeutic methods for diseases such as cancer. We found that suppression of the Hippo pathway in cells changes the characteristics of the surrounding immune cells through an interferon response, thereby significantly changing the immune response from immunosuppression to immunostimulation. Our study proposed a regulatory mechanism by which the Hippo pathway controls the immune system as well as its biological significance.

Academic Significance and Societal Importance of the Research Achievements

免疫系は異物から自己を守る防衛機構として働いており、その機能不全は感染症やがんなどの病態、逆に機能過剰は自己免疫疾患などにつながる。本研究により得られた成果は、細胞内のシグナル伝達経路（＝信号）によって生体の免疫応答がどのように制御されるかという学術的理解を深めるだけでなく、今回解明された個々の分子機構を基盤に将来的な研究を発展させることによって、がんに対する免疫療法などの治療法開発への一助となることも期待される。

Research Products

• [Int'l Joint Research] カリフォルニア大学サンディエゴ校(米国)
• [Int'l Joint Research] University of California, San Diego(米国)
• [Int'l Joint Research] University of California, San Diego/Salk Institute for Biological Studies(米国)
• [Journal Article] The Emerging Link between the Hippo Pathway and Non-coding RNA (2020)
  • Author(s): Shimoda Mayuko、Moroishi Toshiro
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 43 Issue: 1 Pages: 1-10
  • DOI: 10.1248/bpb.b19-00795
  • NAID: 130007779182
  • ISSN: 0918-6158, 1347-5215
  • Year and Date: 2020-01-01
  • Peer Reviewed / Open Access
• [Journal Article] Heat stress activates YAP/TAZ to induce the heat shock transcriptome (2020)
  • Author(s): Luo Min、Meng Zhipeng、Moroishi Toshiro、Lin Kimberly C.、Shen Guobo、Mo Fei、Shao Bin、Wei Xiawei、Zhang Ping、Wei Yuquan、Guan Kun-Liang
  • Journal Title: Nature Cell Biology Volume: 22 Issue: 12 Pages: 1447-1459
  • DOI: 10.1038/s41556-020-00602-9
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The Yin and Yang of tumour-derived extracellular vesicles in tumour immunity (2020)
  • Author(s): Yamauchi Takayoshi、Moroishi Toshiro
  • Journal Title: The Journal of Biochemistry Volume: 169 Issue: 2 Pages: 155-161
  • DOI: 10.1093/jb/mvaa132
  • Peer Reviewed / Open Access
• [Journal Article] Gold Nanoparticles Coimmobilized with Small Molecule Toll-Like Receptor 7 Ligand and α-Mannose as Adjuvants (2019)
  • Author(s): Shinchi Hiroyuki、Yamaguchi Toru、Moroishi Toshiro、Yuki Masaharu、Wakao Masahiro、Cottam Howard B.、Hayashi Tomoko、Carson Dennis A.、Suda Yasuo
  • Journal Title: Bioconjugate Chemistry Volume: 30 Issue: 11 Pages: 2811-2821
  • DOI: 10.1021/acs.bioconjchem.9b00560
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Dual functions of angiopoietin-like protein 2 signaling in tumor progression and anti-tumor immunity. (2019)
  • Author(s): Horiguchi H, Kadomatsu T, Kurahashi R, Hara C, Miyata K, Baba M, Osumi H, Terada K, Araki K, Takai T, Kamba T, Linehan WM, Moroishi T, Oike Y.
  • Journal Title: Genes Dev Volume: 33 Issue: 23-24 Pages: 1641-1656
  • DOI: 10.1101/gad.329417.119
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Hippo Pathway in Mammalian Adaptive Immune System (2019)
  • Author(s): Yamauchi, T., Moroishi, T.
  • Journal Title: Cells Volume: 8 Issue: 5 Pages: 398-398
  • DOI: 10.3390/cells8050398
  • Peer Reviewed / Open Access
• [Journal Article] BRCA1/BARD1-dependent ubiquitination of NF2 regulates Hippo-YAP1 signaling (2019)
  • Author(s): Verma, S., Yeddula, N., Soda, Y., Zhu, Q., Pao, G.M., Moresco, J., Diedrich, J.K., Hong, A., Plouffe, S., Moroishi, T., Guan, K.L., and Verma, I.M.
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 116 Issue: 15 Pages: 7363-7370
  • DOI: 10.1073/pnas.1822155116
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Cell type-dependent function of LATS1/2 in cancer cell growth (2018)
  • Author(s): Pan, W.W., Moroishi, T., Koo,J.H., and Guan, K.L.
  • Journal Title: Oncogene Volume: 38 Issue: 14 Pages: 2595-2610
  • DOI: 10.1038/s41388-018-0610-8
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] RAP2 mediates mechanoresponses of the Hippo pathway (2018)
  • Author(s): Meng, Z., Qiu, Y., Lin, K.C., Kumar, A., Placone, J.K., Fang, C., Wang, K.C., Lu, S., Pan, M., Hong, A.W., Moroishi, T., Luo, M., Plouffe, S.W., Diao, Y., Ye, Z., Park, H.W., Wang, X., Yu, F.X., Chien, S., Wang, C.Y., Ren, B., Engler, A.J., and Guan, K.L.
  • Journal Title: Nature Volume: 560 Issue: 7720 Pages: 655-660
  • DOI: 10.1038/s41586-018-0444-0
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Assembly and activation of the Hippo signalome by FAT1 tumor suppressor (2018)
  • Author(s): Martin, D., Degese, M.S., Vitale-Cross, L., Iglesias-Bartolome, R., Valera, J.L.C., Wang, Z., Feng, X., Yeerna, H., Vadmal, V., Moroishi, T., Thorne, R.F., Zaida, M., Siegele, B., Cheong, S.C., Molinolo, A.A., Samuels, Y., Tamayo, P., Guan, K.L., Lippman, S.M., Lyons, J.G., and Gutkind, J.S.
  • Journal Title: Nature Communications Volume: 9 Issue: 1 Pages: 2372-2372
  • DOI: 10.1038/s41467-018-04590-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Regulation of anti-tumor immunity by extracellular vesicles and the Hippo pathway (2020)
  • Author(s): 諸石寿朗
  • Organizer: 第93回日本生化学会大会
  • Invited
• [Presentation] がん細胞内のシグナルと細胞外小胞による腫瘍微小環境の制御 (2020)
  • Author(s): 諸石寿朗
  • Organizer: 第24回日本がん免疫学会総会
• [Presentation] The Hippo pathway in cancer and immunity (2019)
  • Author(s): Toshiro Moroishi
  • Organizer: TFC International Symposium: Cancer Etiology
  • Int'l Joint Research / Invited
• [Presentation] 細胞外小胞による免疫応答の制御 (2019)
  • Author(s): 諸石寿朗
  • Organizer: 第42回日本分子生物学会年会
  • Invited
• [Presentation] Targeting the Hippo intracellular signaling pathway for cancer immunotherapy (2018)
  • Author(s): Moroishi, T.
  • Organizer: THE 45th NAITO CONFERENCE: Immunological and Molecular Bases for Cancer Immunotherapy
  • Int'l Joint Research
• [Presentation] Hippo経路と細胞外小胞によるがん免疫の制御 (2018)
  • Author(s): 諸石寿朗
  • Organizer: 第41回日本分子生物学会年会
• [Remarks] 熊本大学 大学院生命科学研究部 シグナル・代謝医学講座
  • URL: https://www.moroishi-lab.com
• [Remarks] 熊本大学 大学院生命科学研究部 分子酵素化学講座
  • URL: https://www.moroishi-lab.com