Gao Beixue, Lee Sang-Myeong, Chen An, Zhang Jinping, Zhang Donna D, Kannan Krishnaswamy, Ortmann Robert A, Fang Deyu
Department of Otolaryngology-Head and Neck Surgery, University of Missouri School of Medicine, One Hospital Drive, Columbia, Missouri 65212, USA.
EMBO Rep. 2008 May;9(5):480-5. doi: 10.1038/embor.2008.37. Epub 2008 Mar 28.
The E3 ubiquitin ligase synoviolin (SYVN1) functions as an anti-apoptotic factor that is responsible for the outgrowth of synovial cells during the development of rheumatoid arthritis. The molecular mechanisms underlying SYVN1 regulation of cell death are largely unknown. Here, we report that elevated SYVN1 expression correlates with decreased levels of the protein inositol-requiring enzyme 1 (IRE1)-a pro-apoptotic factor in the endoplasmic reticulum (ER)-stress-induced apoptosis pathway-in synovial fibroblasts from mice with collagen-induced arthritis (CIA). SYVN1 interacts with and catalyses IRE1 ubiquitination and consequently promotes IRE1 degradation. Suppression of SYVN1 expression in synovial fibroblasts from CIA mice restores IRE1 protein expression and reverses the resistance of ER-stress-induced apoptosis of CIA synovial fibroblasts. These results show that SYVN1 causes the overgrowth of synovial cells by degrading IRE1, and therefore antagonizes ER-stress-induced cell death.
E3泛素连接酶滑膜素（SYVN1）作为一种抗凋亡因子，在类风湿性关节炎发展过程中负责滑膜细胞的生长。SYVN1调控细胞死亡的分子机制在很大程度上尚不清楚。在此，我们报道，在胶原诱导性关节炎（CIA）小鼠的滑膜成纤维细胞中，SYVN1表达升高与内质网（ER）应激诱导的凋亡途径中的促凋亡因子——肌醇需求酶1（IRE1）蛋白水平降低相关。SYVN1与IRE1相互作用并催化其泛素化，从而促进IRE1降解。抑制CIA小鼠滑膜成纤维细胞中SYVN1的表达可恢复IRE1蛋白表达，并逆转CIA滑膜成纤维细胞对ER应激诱导的凋亡的抗性。这些结果表明，SYVN1通过降解IRE1导致滑膜细胞过度生长，因此拮抗ER应激诱导的细胞死亡。
