Crosstalk between stress granules and autophagy in protein degradation

• Project/Area Number: 15H04704
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: Niigata University
• Principal Investigator: Fujii Masahiro 新潟大学, 医歯学系, 教授 (30183099)
• Co-Investigator(Kenkyū-buntansha): 小野寺 理 新潟大学, 脳研究所, 教授 (20303167)
• Co-Investigator(Renkei-kenkyūsha): Komatsu Masaaki 新潟大学, 医歯学系, 教授 (90356254)
• Research Collaborator: Takahashi Masahiko ; Kageyama Shun ; Hara Toshifumi ; Higuchi Masaya ; Saito Kousuke ; Koyama Akihide ; Katsuragi Yoshinori ; Kakihana Taichi
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥16,900,000 (Direct Cost: ¥13,000,000、Indirect Cost: ¥3,900,000); Fiscal Year 2017: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2016: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2015: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: ストレス顆粒 / USP10 / 造血幹細胞 / アポトーシス / SCF / G3BP1 / G3BP2 / ストレス / 神経科学 / 癌 / 脳・神経 / 老化 / オートファジー / 脳神経疾患 / TDP-43

Outline of Final Research Achievements

USP10 plays an important role in the formation of stress granule. I established systemic USP10-knockout (USP10-KO) mice. USP10-KO mice developed pancytopenia, and died within 300 days. This pancytopenia was completely restored by transplantation of normal bone marrows into USP10-KO mice. Furthermore, I found that apoptosis of hematopoietic stem cells is aggravated in USP10-KO mice. SCL (stem cell factor) inhibits the apoptosis of hematopoietic stem cells, but this inhibition was significantly attenuated by USP10 depletion in hematopoietic stem cells. USP10 mutants indicated that deubiquitinase activity of USP10 is critical for inhibition of apoptosis of hematopoietic stem cells. The present study suggests that USP10 and stress granules participate in the maintenance of hematopoietic stem cells.

Research Products

• [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
• [Journal Article] Osteopontin-integrin interaction as a novel molecular target for antibody-mediated immunotherapy in adult T-cell leukemia. (2015)
  • Author(s): 1.Maeda N, Ohashi T, Chagan-Yasutan, H, Hattori T, Takahashi Y, Harigae, H, Hasegawa H, Yamada Y, Fujii M, Maenaka K, and Uede T.
  • Journal Title: Retrovirology Volume: 12 Issue: 1 Pages: 99-99
  • DOI: 10.1186/s12977-015-0225-x
  • Peer Reviewed / Open Access
• [Journal Article] Loss of NDRG2 enhanced activation of the NF-κB pathway by PTEN and NIK phosphorylation for ATL and other cancer development. (2015)
  • Author(s): Ichikawa T, Nakahata S, Fujii M, Iha H, Morishita K.
  • Journal Title: Sci Rep Volume: 5 Issue: 1 Pages: 12841-12841
  • DOI: 10.1038/srep12841
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Superoxide-Generating Nox5α Is Functionally Required for the Human T-Cell Leukemia Virus Type 1-Induced Cell Transformation Phenotype. (2015)
  • Author(s): Shigemura T, Shiohara M, Kato M, Furuta S, Kaneda K, Morishita K, Hasegawa H, Fujii M, Gorlach A, Koike K, Kamata T.
  • Journal Title: J Virol. Volume: 89 Issue: 17 Pages: 9080-9
  • DOI: 10.1128/jvi.00983-15
  • Peer Reviewed / Open Access
• [Journal Article] RASAL3, a novel hematopoietic RasGAP protein, regulates the number and functions of NKT cells. (2015)
  • Author(s): Saito S, Kawamura T, Higuchi M, Kobayashi T, Yoshita-Takahashi M, Yamazaki M, Abe M, Sakimura K, Kanda Y, Kawamura H, Jiang S, Naito M, Yoshizaki T, Takahashi M, Fujii M.
  • Journal Title: Eur J Immunol. Volume: in press Issue: 5 Pages: 1512-1523
  • DOI: 10.1002/eji.201444977
  • Peer Reviewed
• [Journal Article] Kruppel-like factor 2 represses transcription of the telomerase catalytic subunit hTERT in human T cells. (2015)
  • Author(s): Hara T, Mizuguchi M, Fujii M, Nakamura M.
  • Journal Title: J Biol Chem Volume: 290(14) Issue: 14 Pages: 8758-8763
  • DOI: 10.1074/jbc.m114.610386
  • Peer Reviewed / Open Access
• [Journal Article] Human T-cell leukemia virus type 1 Tax oncoprotein represses the expression of the BCL11B tumor suppressor in T-cells (2015)
  • Author(s): Takachi T, Takahashi M, Takahashi-Yoshita M, Higuchi M, Obata M, Mishima Y, Okuda S, Tanaka Y, Matsuoka M, Saitoh A, Green PL, Fujii M.
  • Journal Title: Cance Science Volume: 106(4) Issue: 4 Pages: 461-465
  • DOI: 10.1111/cas.12618
  • NAID: 120006844098
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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
• [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: 日本生体防御学会
  • Place of Presentation: 九州大学(福岡県福岡市）
  • Year and Date: 2016-07-07
• [Presentation] HTLV-1 Tax1 oncoprotein but not HTLV-2 Tax2 induces the expression of OX40 ligand by interacting with p52/p100 and RelB (2015)
  • Author(s): Masahiro Fujii, Yosuke Motai, Masaya Higuchi, Toshifumi Hara, Masahiko Takahashi
  • Organizer: 第63回日本ウイルス学会学術集会
  • Place of Presentation: 福岡国際会議場(福岡県福岡市）
  • Year and Date: 2015-11-22
• [Presentation] Ubiquitin Specific Protease 10 is essential for hematopoietic stem cell maintenance (2015)
  • Author(s): Masaya Higuchi, Hiroki Kawamura, Toshifumi Hara, Masahiko Takahashi, Masahiro Fujii
  • Organizer: 第77回日本血液学会学術集会
  • Place of Presentation: ホテル日航金沢（石川県金沢市）
  • Year and Date: 2015-10-16
• [Presentation] Loss of NDRG2 enhanced activation of the NF-κB pathway by PTEN and NIK phosphorylation for ATLL development (2015)
  • Author(s): Ichikawa T, Nakahata S, Fujii M, Iha H, Morishita K.
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場(愛知県名古屋市）
  • Year and Date: 2015-10-08
• [Presentation] HTLV-1のTax1はHTLV-2のTax2とは異なる細胞遺伝子の発現をNF-kB2を介して誘導する (2015)
  • Author(s): 藤井雅寛、罇陽介、原俊文、高橋雅彦
  • Organizer: 第2回日本HTLV-1学会学術集会
  • Place of Presentation: 東京大学医科学研究所（東京都港区）
  • Year and Date: 2015-08-22