Molecularbasis of fibrosis by ERAD CER associated protein degradation.

2012 Fiscal Year Final Research Report

• 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
• Keywords: 分子病態学

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 Pages: 1281-1286
  • DOI: 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(53) Pages: 44203-11
  • DOI: 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): Usui C, Hatta K, Aratani S, Yagishita N, Nishioka K, Kanazawa T, Ito K, Yamano Y, Nakamura H, Nakajima T, Nishioka K
  • Journal Title: Mod.Rheumatol Volume: 22 Pages: 40-44
  • DOI: DOI:10.1007/s10165-011-0462-3
  • Peer Reviewed
• [Journal Article] Fucoidan therapy decreases the proviral load in patients with human T-lymphotropic virus type1-associated neurological disease. (2011)
  • Author(s): Araya N, Takahashi K, Sato T, Nakamura T, Sawa C, Hasegawa D, Ando H, Aratani S, Yagishita N, Fujii R, Oka H, Nishioka K, Nakajima T, Mori N, Yamano Y
  • Journal Title: Antiviral Therapy Volume: 16(1) Pages: 89-98
  • DOI: DOI:10.3892/ijmm_00000271
  • 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: Annals of the Rheumatic Diseases Volume: 70(1) Pages: 221-226
  • DOI: 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): Sato T, Fujii R, Konomi K, Yagishita N, Aratani S, Araya N, Aono H, Yudoh K, Suzuki N, Beppu M, Yamano Y, Nishioka K, Nakajima T
  • Journal Title: Arthritis Rheum Volume: 63(12) Pages: 3833-3842
  • DOI: DOI:10.1002/art.30617
  • Peer Reviewed
• [Journal Article] Stringent requirement for HRD1, SEL1L, and OS-9/XTP3-B for disposal of ERAD-LS substrate (2010)
  • Author(s): Bernasconi R, Galli C, Calanca V, Nakajima T, Molinari M
  • Journal Title: J Cell Biol Volume: 188(2) Pages: 223-35
  • DOI: DOI:10.1083/jcb.200910042
  • 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.
  • Year and Date: 20120723-25
• [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
  • Year and Date: 20110711-13
• [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
  • Year and Date: 20110711-13
• [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 Number: 2012-283-763
  • Filing Date: 2012-12-26