Molecularbasis of fibrosis by ERAD CER associated protein degradation.

风湿性关节炎（RA）严重影响生活质量。我们最近克隆了滑液素，一种环型E3泛素连接酶，参与内质网相关降解（ERAD）途径。滑膜蛋白在类风湿关节炎滑膜细胞中高表达，可能参与类风湿关节炎的发病机制。抑制滑膜蛋白活性是治疗RA的潜在有用的治疗方法。我们进行了一个高通量的小分子筛选，以找到抑制剂的滑膜蛋白autoubiquitination活动。我们鉴定了两类小分子，命名为LS-101和LS-102，它们抑制滑液蛋白活性。LS-102选择性抑制滑液蛋白酶活性，而LS-101抑制广泛的RING型E3连接酶。此外，这些物质抑制类风湿性关节炎滑膜细胞的增殖，并显着降低疾病的严重程度，在小鼠模型的RA。我们的研究结果表明，抑制滑膜是一个潜在的有用的方法在治疗类风湿关节炎。

Rheumatoid arthritis (RA) significantly affects quality of life. We recently cloned synoviolin, a RING-type E3 ubiquitin ligase implicated in the endoplasmic reticulum-associated degradation (ERAD) pathway. Synoviolin is highly expressed in rheumatoid synovial cells and may be involved in the pathogenesis of RA. Inhibition of synoviolin activity is a potentially useful therapeutic approach for the treatment of RA. We conducted a high-throughput screen of small molecules to find inhibitors of synoviolin autoubiquitination activity. We identified two classes of small molecules, named LS-101 and LS-102, which inhibited synoviolin activity. LS-102 selectively inhibited synoviolin enzymatic activity, while LS-101 inhibited a broad array of RING-type E3 ligases. Moreover, these inhibitorssuppressed the proliferation of rheumatoid synovial cells, and significantly reduced the severity of disease in a mouse model of RA. Our results suggest that inhibition of synoviolin is a potentially useful approach in the treatment of RA.