Elucidation of a novel molecular mechanism that suppresses sensitivity to proteasome inhibitors

• Project/Area Number: 17K09918
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Niigata University
• Principal Investigator: Takahashi Masahiko 新潟大学, 医歯学系, 准教授 (80377192)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: USP10 / 成人T細胞白血病 / パーキンソン病 / HTLV-1 / ATL

Outline of Final Research Achievements

Adult T-cell leukemia (ATL) is a CD4-positive T-cell leukemia caused by infection of human T-cell leukemia virus type 1 (HTLV-1). We identified ubiquitin-specific protease 10 (USP10) as a cellular factor that binds to the HTLV-1 Tax protein. In ATL cells, reduced USP10 expression promoted apoptosis induced by proteasome inhibitor, indicating that USP10 enhances ATL cell viability. Analysis of this molecular mechanism revealed that USP10 aggregates cytotoxic ubiquitinated proteins to form aggresome and inactivates the toxicity.

Academic Significance and Societal Importance of the Research Achievements

ユビキチン化蛋白の蓄積は、癌および神経変性疾患を含む様々な病態に関与する。しかしながら、ユビキチン化蛋白の蓄積がどのように病態に関わるのか、その分子機構は不明な点が多い。本研究により得られた結果は、癌および神経変性疾患における異常蛋白が細胞毒性を誘導する分子機構について、基礎的情報を提供する。また、USP10が異常蛋白の細胞毒性を低下させることから、USP10を分子標的とした治療薬開発に応用可能な情報を提供できる。

Research Products

• [Journal Article] G3BP1 inhibits ubiquitinated protein aggregations induced by p62 and USP10 (2019)
  • Author(s): Anisimov S, Takahashi M, Kakihana T, Katsuragi Y, Kitaura H, Zhang L, Kakita A, Fujii M.
  • Journal Title: Sci Rep Volume: 9(1) Issue: 1 Pages: 12896-12896
  • DOI: 10.1038/s41598-019-46237-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] USP10 is a critical factor for Tau-positive stress granule formation in neuronal cells (2019)
  • Author(s): Piatnitskaia S, Takahashi M, Kitaura H, Katsuragi Y, Kakihana T, Zhang L, Kakita A, Iwakura Y, Nawa H, Miura T, Ikeuchi T, Hara T, Fujii M
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 10591-10591
  • DOI: 10.1038/s41598-019-47033-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] USP10はアグリソームの形成を誘導し、ユビキチン化蛋白質オリゴマーの細胞毒性を抑制する (2019)
  • Author(s): 高橋雅彦、Piatnitskaia Svetlana, Anisimov Sergei, 藤井雅寛
  • Journal Title: 新潟医学会雑誌 Volume: 133 Pages: 91-96
  • NAID: 120006840411
• [Journal Article] USP10 Is a Driver of Ubiquitinated Protein Aggregation and Aggresome Formation to Inhibit Apoptosis. (2018)
  • Author(s): Takahashi M, Kitaura H, Kakita A, Kakihana T, Katsuragi Y, Nameta M, Zhang L, Iwakura Y, Nawa H, Higuchi M, Komatsu M, Fujii M.
  • Journal Title: iScience Volume: 30 Pages: 433-450
  • DOI: 10.1016/j.isci.2018.11.006
  • Peer Reviewed / Open Access
• [Journal Article] MAGI-1 expression is decreased in several types of human T-cell leukemia cell lines, including adult T-cell leukemia. (2018)
  • Author(s): Kozakai T, Takahashi M, Higuchi M, Hara T, Saito K, Tanaka Y, Masuko M, Takizawa J, Sone H, Fujii M
  • Journal Title: International Journal of Hematology Volume: 107(3) Issue: 3 Pages: 337-344
  • DOI: 10.1007/s12185-017-2359-1
  • Peer Reviewed / Open Access
• [Presentation] USP10 IS A CRITICAL FACTOR IN α-SYNUCLEIN AGGREGATION, AGGRESOME AND LEWY BODY FORMATIONS BUT NOT GCI (2019)
  • Author(s): Masahiko Takahashi, Hiroki Kitaura, Akiyoshi Kakita, Taichi Kakihana, Yoshinori Katsuragi, Masaaki Nameta, Yuriko Iwakura, Hiroyuki Nawa, Masaya Higuchi, Masaaki Komatsu, Masahiro Fujii
  • Organizer: 24th World Congress of Neurology
  • Int'l Joint Research
• [Remarks] 新潟大学大学院 医歯学総合研究科 ウイルス学分野 ホームページ