Cloning of Synoviolin We identified Synoviolin from a human cDNA library of rheumatoid synovial cells (RSC) by immunoscreening with anti-RSC antibodies to isolate a molecule promoting the autonomous proliferation and activation of synovial cells in RA

We introduce Synoviolin as a novel pathogenic factor in rheumatoid arthritis (RA). Experimental studies indicate that this endoplasmic reticulum (ER)-resident E3 ubiquitin ligase has important functions in the ER-associated degradation (ERAD) system, an essential system for ER homeostasis. Overexpression of Synoviolin in mice causes arthropathy with synovial hyperplasia, whereas heterozygous knockdown results in increased apoptosis of synovial cells and resistance to collagen-induced arthritis in mice. On the basis of these experimental data, we propose that excess elimination of unfolded proteins (that is, ‘hyper-ERAD’) by overexpression of Synoviolin triggers synovial cell overgrowth and hence a worsening of RA. Further analysis of the hyper-ERAD system may permit the complex pathomechanisms of RA to be uncovered. Introduction There is a general agreement that synovial cells have a crucial function in rheumatoid arthritis (RA) by forming a mass of synovial tissue, which promotes the production of matrixdegrading proteases and osteoclast activation that lead to joint destruction [1-6]. In a series of experiments that focused on synovial cells, we determined that human T cell leukemia virus type I (HTLV-I) causes arthropathy [7], and that tax, the viral transforming gene of HTLV-1, and its product, pp40Tax, could transform synovial cells of patients as well as those of tax-overexpressing mice [8-10]. These results suggest that synoviocytes can acquire the ability to overgrow autonomously in RA. Here we discuss the role of a novel pathogenic factor for RA named ‘Synoviolin’ (GenBank accession no. AB024690) [11]. This novel molecule is an endoplasmic reticulum (ER)resident ubiquitin ligase and is involved in the ER-associated degradation (ERAD) system [12-17]. ERAD is an important processing system for ER homeostasis, and its disruption is known to result in cellular apoptosis [18]. Surprisingly, both the amount and enzymatic activity of Synoviolin regulate synovial cell proliferation and apoptosis, at least in mice [11]. Cloning of Synoviolin We identified Synoviolin from a human cDNA library of rheumatoid synovial cells (RSC) by immunoscreening with anti-RSC antibodies to isolate a molecule promoting the autonomous proliferation and activation of synovial cells in RA [11]. Structurally, Synoviolin has a putative six-transmembrane domain and a RING-H2 motif (Fig. 1). As reported previously, proteins with a RING finger domain act as E3 ubiquitin ligases [19], Synoviolin also exhibits a clear autoubiquitination activity [11]. By using immunostaining, we also determined that Synoviolin is located in the ER of synovial cells. We therefore concluded that Synoviolin is an ERresident E3 ubiquitin ligase [11]. Previous studies in yeast and human cells concluded that ERresident E3 ubiquitin ligases are important for ER homeostasis [20]. Because it is estimated that 30 to 40% of the newly synthesized proteins fail to fold properly in the ER [21], these unfolded proteins eventually induce severe damage of the ER (so-called ER stress) or even apoptosis of the cell (ER stress-induced apoptosis) unless two biological processes, unfolded protein response (UPR) and ERAD, work properly [20,22,23]. In brief, UPR contains two systems involved in the attenuation of global translation to stop the influx of proteins into the ER and increasing the transcription of chaperones to refold the unfolded proteins in the ER again. In contrast, the ERAD system eliminates unfolded proteins that Commentary Rheumatoid arthritis as a hyper-endoplasmic reticulumassociated degradation disease Satoshi Yamasaki1, Naoko Yagishita1, Kaneyuki Tsuchimochi1, Kusuki Nishioka2 and Toshihiro Nakajima1 1Department of Genome Science, Institute of Medical Science, St Marianna University School of Medicine, Kawasaki, Kanagawa, Japan 2Rheumatology, Immunology and Genetics Program, Institute of Medical Science, St Marianna University School of Medicine, Kawasaki, Kanagawa, Japan Corresponding author: Toshihiro Nakajima, [email protected] Published: 17 August 2005 Arthritis Research & Therapy 2005, 7:181-186 (DOI 10.1186/ar1808) This article is online at http://arthritis-research.com/content/7/5/181 © 2005 BioMed Central Ltd