Synoviolin/Hrd1, an E3 ubiquitin ligase, as a novel pathogenic factor for arthropathy

  1. Tetsuya Amano1,6,
  2. Satoshi Yamasaki1,6,
  3. Naoko Yagishita1,6,
  4. Kaneyuki Tsuchimochi1,4,
  5. Hiroshi Shin3,
  6. Ko-ichi Kawahara5,
  7. Satoko Aratani1,
  8. Hidetoshi Fujita1,3,
  9. Lei Zhang1,
  10. Rie Ikeda1,
  11. Ryoji Fujii1,
  12. Naoki Miura5,
  13. Setsuro Komiya4,
  14. Kusuki Nishioka2,
  15. Ikuro Maruyama5,
  16. Akiyoshi Fukamizu3, and
  17. Toshihiro Nakajima1,7
  1. 1 Department of Genome Science Institute of Medical Science, St. Marianna University School of Medicine, Kawasaki, Kanagawa 216-8512, Japan
  2. 2 Rheumatology, Immunology and Genetics Program, Institute of Medical Science, St. Marianna University School of Medicine, Kawasaki, Kanagawa 216-8512, Japan
  3. 3 Institute of Applied Biochemistry and Center for Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan
  4. 4 Department of Orthopedic Surgery Kagoshima University, Faculty of Medicine, Kagoshima 890-8520, Japan
  5. 5 Department of Dermatology and Laboratory of Molecular Medicine, Kagoshima University, Faculty of Medicine, Kagoshima 890-8520, Japan

Abstract

Rheumatoid arthritis (RA) is one of the most critical articular diseases with synovial hyperplasia followed by impairment of quality of life. However, the mechanism(s) that regulates synovial cell outgrowth is not fully understood. To clarify its mechanism(s), we carried out immunoscreening by using antirheumatoid synovial cell antibody and identified and cloned “Synoviolin/Hrd1”, an E3 ubiquitin ligase. Synoviolin/Hrd1 was highly expressed in the rheumatoid synovium, and mice overexpressing this enzyme developed spontaneous arthropathy. Conversely, synoviolin/hrd1+/- mice were resistant to collagen-induced arthritis by enhanced apoptosis of synovial cells. We conclude that Synoviolin/Hrd1 is a novel causative factor for arthropathy by triggering synovial cell outgrowth through its antiapoptotic effects. Our findings provide a new pathogenetic model of RA and suggest that Synoviolin/Hrd1 could be targeted as a therapeutic strategy for RA.

Keywords

Footnotes

  • Article published online ahead of print. Article and publication date are at http://www.genesdev.org/cgi/doi/10.1101/gad.1096603.

  • ↵6 These authors contributed equally to this work.

  • ↵7 Corresponding author. E-MAIL nakashit{at}marianna-u.ac.jp; FAX 81-44-977-9772.

    • Accepted August 4, 2003.
    • Received March 24, 2003.
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This Article

  1. Published in Advance January 1, 2003, doi: 10.1101/gad.1096603 Genes & Dev. 17: 2436-2449 Cold Spring Harbor Laboratory Press

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