Lei Zhang

Publications (2)20.86 Total impact

• Article: Cytoplasmic destruction of p53 by the endoplasmic reticulum-resident ubiquitin ligase 'Synoviolin'.

  Satoshi Yamasaki, Naoko Yagishita, Takeshi Sasaki, Minako Nakazawa, Yukihiro Kato, Tadayuki Yamadera, Eunkyung Bae, Sayumi Toriyama, Rie Ikeda, Lei Zhang, [......], Haruki Senoo, Takahiro Ochi, Shigeyuki Yokoyama, Tetsuya Amano, Jaeseob Kim, Steffen Gay, Akiyoshi Fukamizu, Kusuki Nishioka, Keiji Tanaka, Toshihiro Nakajima
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  ABSTRACT: Synoviolin, also called HRD1, is an E3 ubiquitin ligase and is implicated in endoplasmic reticulum -associated degradation. In mammals, Synoviolin plays crucial roles in various physiological and pathological processes, including embryogenesis and the pathogenesis of arthropathy. However, little is known about the molecular mechanisms of Synoviolin in these actions. To clarify these issues, we analyzed the profile of protein expression in synoviolin-null cells. Here, we report that Synoviolin targets tumor suppressor gene p53 for ubiquitination. Synoviolin sequestrated and metabolized p53 in the cytoplasm and negatively regulated its cellular level and biological functions, including transcription, cell cycle regulation and apoptosis. Furthermore, these p53 regulatory functions of Synoviolin were irrelevant to other E3 ubiquitin ligases for p53, such as MDM2, Pirh2 and Cop1, which form autoregulatory feedback loops. Our results provide novel insights into p53 signaling mediated by Synoviolin.
  The EMBO Journal 02/2007; 26(1):113-22. · 9.20 Impact Factor
• Article: Synoviolin/Hrd1, an E3 ubiquitin ligase, as a novel pathogenic factor for arthropathy.

  Tetsuya Amano, Satoshi Yamasaki, Naoko Yagishita, Kaneyuki Tsuchimochi, Hiroshi Shin, Ko-ichi Kawahara, Satoko Aratani, Hidetoshi Fujita, Lei Zhang, Rie Ikeda, Ryoji Fujii, Naoki Miura, Setsuro Komiya, Kusuki Nishioka, Ikuro Maruyama, Akiyoshi Fukamizu, Toshihiro Nakajima
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  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.
  Genes & Development 11/2003; 17(19):2436-49. · 11.66 Impact Factor