Yamasaki Satoshi, Yagishita Naoko, Tsuchimochi Kaneyuki, Kato Yukihiro, Sasaki Takeshi, Amano Tetsuya, Beppu Moroe, Aoki Haruhito, Nakamura Hiroshi, Nishioka Kusuki, Nakajima Toshihiro
Department of Genome Science, Institute of Medical Science, St. Marianna University School of Medicine, Kawasaki, Kanagawa 216-8512, Japan.
Int J Mol Med. 2006 Jul;18(1):113-7.
Synoviolin is an endoplasmic reticulum (ER)-resident E3 ubiquitin ligase which plays a critical role in ER-associated degradation (ERAD). We found that Synoviolin is a novel causative factor for rheumatoid arthritis (RA), which is especially up-regulated in proliferating synovial cells in the disease. We attempted to examine the role of Synoviolin in ER stress-induced apoptosis and proliferation of synovial cells. RA synovial cells (RSCs) were refractory to ER stress-induced apoptosis compared with HEK293 or HeLa cells. RSCs were also more resistant to the apoptosis than synovial cells from osteoarthritis patients, significantly. Down-regulation of Synoviolin by siRNA increased the susceptibility to ER stress-induced apoptosis in RSCs. Knock-down of Synoviolin by siRNA did not only induce apoptosis of RSCs but also inhibited their proliferation in vitro. These data suggest that RSCs are extraordinarily refractory to ER stress-induced apoptosis, and we termed this special property 'hyper-ERAD'. Since Synoviolin is overexpressed in RSCs, and is known to play a critical role in the ERAD system as E3 ubiquitin ligase, hyper-ERAD is likely to present in these cells. Subsequently, the hyper-ERAD may cause synovial hyperplasia through its anti-apoptotic effect in RA. Further analyses are necessary to address this point, however, resistance to ER stress-induced apoptosis, or hyper-ERAD is a noteworthy new cellular characteristic of RSCs.
滑膜素是一种内质网驻留的E3泛素连接酶，在与内质网相关的降解（ERAD）中起关键作用。我们发现滑膜素是类风湿性关节炎（RA）的一种新的致病因素，在该疾病中增殖的滑膜细胞中尤其上调。我们试图研究滑膜素在内质网应激诱导的滑膜细胞凋亡和增殖中的作用。与HEK293或HeLa细胞相比，RA滑膜细胞（RSCs）对内质网应激诱导的凋亡具有抗性。RSCs也比骨关节炎患者的滑膜细胞对凋亡更具抗性，差异显著。通过小干扰RNA（siRNA）下调滑膜素可增加RSCs对内质网应激诱导凋亡的敏感性。用siRNA敲低滑膜素不仅诱导RSCs凋亡，还抑制其体外增殖。这些数据表明，RSCs对内质网应激诱导的凋亡具有极强的抗性，我们将这种特殊性质称为“内质网相关降解亢进（hyper-ERAD）”。由于滑膜素在RSCs中过表达，且已知作为E3泛素连接酶在ERAD系统中起关键作用，内质网相关降解亢进可能存在于这些细胞中。随后，内质网相关降解亢进可能通过其在RA中的抗凋亡作用导致滑膜增生。然而，需要进一步分析来阐明这一点，对内质网应激诱导凋亡的抗性，即内质网相关降解亢进，是RSCs一个值得注意的新细胞特征。
