Molecularbasis of fibrosis by ERAD CER associated protein degradation.

• Project/Area Number: 23659176
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Pathological medical chemistry
• Research Institution: Tokyo Medical University
• Principal Investigator: NAKAJIMA Toshihiro 東京医科大学, 医学部, 教授 (90260752)
• Project Period (FY): 2011 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2012: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2011: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 分子病態学 / 線維化 / 小胞体関連分解 / 関節リウマチ / 滑膜細胞 / シノビオリン / コンディショナルノックアウトマウス / ンディショナルノックアウトマウス

Research Abstract

Rheumatoid arthritis (RA) significantly affects quality of life. We recently cloned synoviolin, a RING-type E3 ubiquitin ligase implicated in the endoplasmic reticulum-associated degradation (ERAD) pathway. Synoviolin is highly expressed in rheumatoid synovial cells and may be involved in the pathogenesis of RA. Inhibition of synoviolin activity is a potentially useful therapeutic approach for the treatment of RA. We conducted a high-throughput screen of small molecules to find inhibitors of synoviolin autoubiquitination activity. We identified two classes of small molecules, named LS-101 and LS-102, which inhibited synoviolin activity. LS-102 selectively inhibited synoviolin enzymatic activity, while LS-101 inhibited a broad array of RING-type E3 ligases. Moreover, these inhibitorssuppressed the proliferation of rheumatoid synovial cells, and significantly reduced the severity of disease in a mouse model of RA. Our results suggest that inhibition of synoviolin is a potentially useful approach in the treatment of RA.

Research Products

• [Journal Article] RING-finger type E3 ubiquitin ligase inhibitors as novel candidates for the treatment of rheumatoid arthritis. (2012)
  • Author(s): Yagishita N., Aratani S., Leach C., Amano T., Yamano Y., Nakatani K., Nishioka K. and Nakajima T
  • Journal Title: Int. J. Mol. Med Volume: 30 Issue: 6 Pages: 1281-1286
  • DOI: 10.3892/ijmm.2012.1129
  • Peer Reviewed
• [Journal Article] The ubiquitin ligase synoviolin up-regulates amyloid β production by targeting a negative regulator of γ-secretase, Rer1, for degradation. (2012)
  • Author(s): Tanabe C, Maeda T, Zou K, Liu J, Liu S, Nakajima T, Komano H.
  • Journal Title: J Biol Chem. Volume: 287 Issue: 53 Pages: 44203-44211
  • DOI: 10.1074/jbc.m112.365296
  • Peer Reviewed
• [Journal Article] The Japanese version of the 2010 American College of Rheumatology Preliminary Diagnostic Criteria for Fibromyalgia and the Fibromyalgia Symptom Scale : reliability and validity (2012)
  • Author(s): 臼井千恵、中島利博, 他9名
  • Journal Title: Mod.Rheumatol. Volume: 20 Issue: 1 Pages: 40-44
  • DOI: 10.1007/s10165-011-0462-3
  • NAID: 10030206754
  • Peer Reviewed
• [Journal Article] Prostaglandin EP2 receptor signalling inhibits the expression of matrix metalloproteinase 13 in human osteoarthritic chondrocytes (2011)
  • Author(s): Sato T, Konomi K, Fujii R, Aono H, Aratani S, Yagishita N, Araya N, Yudoh K, Beppu M, Yamano Y, Nishioka K, Nakajima T
  • Journal Title: Ann Rheum Dis Volume: 70 Issue: 1 Pages: 221-22
  • DOI: 10.1136/ard.2009.118620
  • Peer Reviewed
• [Journal Article] Overexpression of SPACIA1/SAAL1, a new gene that is involved in synoviocyte proliferation, accelerates the progression of synovitis in mice and humans (2011)
  • Author(s): 佐藤知雄、中島利博, 他11名
  • Journal Title: Arthritis Rheum Volume: 63 Issue: 12 Pages: 3833-3842
  • DOI: 10.1002/art.30617
  • Peer Reviewed
• [Journal Article] Stringent requirement for HRD1, SEL1L, and OS-9/XTP3-B for disposal of ERAD-LS substrates (2010)
  • Author(s): Bernasconi R, Galli C, Calanca V, Nakajima T, Molinari M.
  • Journal Title: J Cell Biol Volume: 188 Issue: 2 Pages: 223-235
  • DOI: 10.1083/jcb.200910042
  • Peer Reviewed
• [Journal Article] Role of Kenae/CCDC125 in cell motility through the deregulation of RhoGTPase (2009)
  • Author(s): Araya N, Arimura H, Kawahara K, Yagishita N, Ishida J, Fujii R, Aratani S, Fujita H, Sato T, Yamano Y, Higuchi I, Osame M, Nishioka K, Fukamizu A, Arimura K, Maruyama I, Nakajima T.
  • Journal Title: Int J Mol Med Volume: 24 Issue: 05 Pages: 605-611
  • DOI: 10.3892/ijmm_00000271
  • Peer Reviewed
• [Presentation] What tells us from Post-neonatal knock out of synoviolin (2012)
  • Author(s): Toshihiro Nakajima, Naoko Yagishita, Satoko Aratani, Hidetoshi Fujita, Kusuki Nishioka
  • Organizer: 4th Annual Ubiquitin Drug Discovery & Diagnostics Conference 2012
  • Place of Presentation: Four Seasons Hotel Philadelphia, USA.
• [Presentation] Synoviolin (2011)
  • Author(s): Toshihiro Nakajima
  • Organizer: a novel regulator for fibrosis3rd Annual Ubiquitin Drug Discovery & Diagnostics Conference 2011
  • Place of Presentation: Four Seasons Hotel Philadelphia, USA
• [Presentation] E3 Ubiquitin Ligase Synoviolin Is Involved in Liver Fibrogenesis (2011)
  • Author(s): Satoko Aratani, Daisuke Hasegawa, NaokoYagishita, Kusuki Nishioka, Toshihiro Nakajima
  • Organizer: 3rd Annual Ubiquitin Drug Discovery & Diagnostics Conference 2011
  • Place of Presentation: Four Seasons Hotel Philadelphia, USA
• [Presentation] Synoviolin ; a novel regulator for fibrosis. (2011)
  • Author(s): 中島 利博 他4名
  • Organizer: Ubiquitin Drug Discovery and Diagnostics2011(招待講演)
  • Place of Presentation: Four Seasons Hotel,Philadelphia.PA.USA
• [Presentation] ER stress signaling as a chronicity of imflammation. (2011)
  • Author(s): 中島 利博 他5名
  • Organizer: 2nd Tokyo-Shanghai Rheumatology Workshop(招待講演)
  • Place of Presentation: Hilton Tokyo Bay Hotel
• [Presentation] Locomotive syndrome meets metabolic syndrome. (2011)
  • Author(s): 中島 利博
  • Organizer: 1st Bio- RheumatologyInternationalCongress(BRIC)Tokyo/the 8th GARN Meeting(招待講演)
  • Place of Presentation: HiltonTokyoBayHotel
• [Remarks]
  • URL: http://www.tokyo-med.ac.jp/rrc/
• [Patent(Industrial Property Rights)] 1,3,5-トリアジン誘導体を有する線維化予防又は治療剤 (2012)
  • Inventor(s): 中島利博、瀬戸口靖弘、中島若巳、荒谷聡子、藤田英俊
  • Industrial Property Rights Holder: 学校法人 東京医科大学
  • Filing Date: 2012-12-26
• [Patent(Industrial Property Rights)] １，３，５―トリアジン誘導体を有する線維化予防又は治療剤 (2012)
  • Inventor(s): 中島利博、瀬戸口靖弘、中島若巳、荒谷聡子、藤田英俊
  • Industrial Property Rights Holder: 学校法人 東京医科大学
  • Industrial Property Rights Type: 特許
  • Filing Date: 2012-12-26