ROS production regulation by stress granule

• Project/Area Number: 16K15502
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Hematology
• Research Institution: Niigata University
• Principal Investigator: FUJII MASAHIRO 新潟大学, 医歯学系, 教授 (30183099)
• Research Collaborator: TAKAHASHI masahiko
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2016: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
• Keywords: ストレス顆粒 / アグリソーム / 活性酸素 / 蛋白質凝集体 / アルツハイマー / タウ / パーキンソン病 / シヌクレイン / レビー小体 / 凝集体 / アルツハイマー病 / USP10 / G3BP1 / G3BP2 / ウイルス / 癌

Outline of Final Research Achievements

USP10 promotes the conversion of ubiquitinated protein oligomers into aggresomes, and suppresses the cytotoxicity of ubiquitinated protein oligomers. 2) p62 binds to various ubiquitinated proteins and induces protein aggregate formation. USP10 binds to p62 and augments p62-induced protein aggregation. 3) Tau is a pathogenic protein of Alzheimer's disease (AD). USP10 induces Tau-positive stress granule formation, which initiates Tau aggregation in AD. 4) USP10 is a factor for initiating the formation of Lewy bodies (α-synuclein aggregates) in Parkinson's disease.
Protein aggregates are involved in the onset of various diseases including neurodegenerative and neoplastic diseases. The present study suggested that USP10 is involved in the formation of protein aggregates through the formation of stress granules and aggresomes.

Academic Significance and Societal Importance of the Research Achievements

異常な蛋白質凝集体は、神経変性疾患、腫瘍性疾患を含む様々な疾患の発症に関与する。例えば、アルツハイマー病およびパーキンソン病などである。生理的あるいは病的蛋白質凝集体の形成にストレス顆粒およびアグレソームが関与する。本研究は、USP10が、ストレス顆粒およびアグレソームの形成を通して、生理的および病的な蛋白質凝集体の形成に関与することを明らかにした。USP10とストレス顆粒は活性酸素の産生を抑制する。従って、USP10は蛋白質凝集体の形成と活性酸素の制御を繋ぐキー因子であることが示唆された。

Research Products

• [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
• [Journal Article] Sox2-dependent inhibition of p21 is associated with poor prognosis of endometrial cancer. (2017)
  • Author(s): Yamawaki K, Ishiguro T, Mori Y, Yoshihara K, Suda K, Tamura R, Yamaguchi M, Sekine M, Kashima K, Higuchi M, Fujii M, Okamoto K, Enomoto T
  • Journal Title: Cancer Sci. Volume: 108 Issue: 4 Pages: 632-640
  • DOI: 10.1111/cas.13196
  • Peer Reviewed / Open Access
• [Journal Article] USP10 Is an Essential Deubiquitinase for Hematopoiesis and Inhibits Apoptosis of Long-Term Hematopoietic Stem Cells. (2016)
  • Author(s): Higuchi M, Kawamura H, Matsuki H, Hara T, Takahashi M, Saito S, Saito K, Jiang S, Naito M, Kiyonari H, Fujii M.
  • Journal Title: Stem Cell Reports Volume: ７ Issue: 6 Pages: 1116-1129
  • DOI: 10.1016/j.stemcr.2016.11.003
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Human T-cell leukemia virus type 1 (HTLV-1) Tax1 oncoprotein but not HTLV-2 Tax2 induces the expression of OX40 ligand by interacting with p52/p100 and RelB. (2016)
  • Author(s): Motai Y, Takahashi M, Takachi T, Higuchi M, Hara T, Mizuguchi M, Aoyagi Y, Terai S, Tanaka Y, Fujii M.
  • Journal Title: Virus Genes. Volume: 52 Issue: 1 Pages: 4-13
  • DOI: 10.1007/s11262-015-1277-7
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Induction of Cell Death by Human T-cell Leukemia Virus Type 1 Tax in a Cell Cycle-Dependent Manner. (2016)
  • Author(s): Mizuguchi M, Sasaki Y, Hara T, Higuchi M, Tanaka Y, Funato N, Tanaka N, Fujii M, Nakamura M.
  • Journal Title: PLoS One Volume: 11 Issue: 2 Pages: 0148217-0148217
  • DOI: 10.1371/journal.pone.0148217
  • Peer Reviewed / Open Access
• [Presentation] Role of ROS in pathogenesis of HTLV-1-associated diseases (2018)
  • Author(s): 藤井雅寛
  • Organizer: Frontiers in Retrovirology Conference 2018
  • Int'l Joint Research / Invited
• [Presentation] Signal transduction of reactive oxygen species in HAM and ATL (2017)
  • Author(s): 藤井雅寛、高橋雅彦、樋口雅也
  • Organizer: 日本HTLV-1学会学術集会
  • Invited
• [Presentation] Stress granules and autophagy control degradation of neuropathogenic RNA-binding proteins (2017)
  • Author(s): Masahiro Fujii, Toshifumi Hara, Masaya Higuchi, Osamu Onodera, Masahiko Takahashi
  • Organizer: 日本神経科学学会
• [Presentation] ストレス顆粒とオートファジーによる酸化ストレスの制御機構 (2017)
  • Author(s): 藤井雅寛, 原敏文、樋口雅也、高橋雅彦
  • Organizer: 日本抗加齢医学会
  • Invited
• [Presentation] 脱ユビキチン化酵素USP10はHematopoietic stem cellの恒常性維持に必須である (2016)
  • Author(s): 川村 宏樹、樋口 雅也、藤井 雅寛
  • Organizer: 第27回日本生体防御学会学術総会
  • Place of Presentation: 九州大学（福岡県福岡市）
  • Year and Date: 2016-07-07
• [Remarks] パーキンソン病において神経病原性蛋白質を不活化する蛋白質を同定
  • URL: https://www.med.niigata-u.ac.jp/contents/info/news_topics/93_index.html