Department of Locomotor Science, Institute of Medical Science, Tokyo Medical University, Tokyo 160‑8402, Japan.
Department of Rare Diseases Research, Institute of Medical Science, St. Marianna University School of Medicine, Kawasaki, Kanagawa 216‑8512, Japan.
Mol Med Rep. 2017 Dec;16(6):9203-9209. doi: 10.3892/mmr.2017.7764. Epub 2017 Oct 11.
Rheumatoid arthritis (RA) is a chronic inflammatory articular disease that is characterized by synovial hyperplasia. A number of signaling pathways are associated with the development and induced symptoms of RA. Notably, patients with RA have increased protein citrullination and generation of auto‑antibodies against citrullinated proteins. Genome wide association studies have revealed that peptidyl‑arginine deiminase 4 (PADI4) is an enzyme implicated in citrullination in the RA synovium. Autoantibodies targeting citrullinated proteins are used as diagnostic markers in patients with RA. The functions associated with citrullinated proteins are thought to induce autoimmunity, however, the regulatory mechanisms of citrullination via PADI4 are unclear. The group has previously cloned an E3 ubiquitin ligase, synoviolin (SYVN1), from the RA synovium, demonstrating that SYVN1 serves critical roles in synovial hyperplasia. The data indicated that the endoplasmic reticulum (ER) associated degradation system, which involves SYVN1, may have important roles in the proliferation of synoviocytes. In addition, ubiquitination by SYVN1 is associated with fibrosis, inflammation and cytokine production via the regulation of ER stress signals and quality control of proteins. The present study investigated the crosstalk between the representative post‑translational signaling processes, citrullination and ubiquitination. The results revealed that PADI4 interacted with SYVN1 directly and that overexpression of PADI4 suppressed the ubiquitination of proteins. Thus, a reduction in ER stress induced by PADI4 may abrogate the initiation of chronic RA by suppressing the proliferative signals of RA synoviocytes.
类风湿关节炎（RA）是一种慢性炎症性关节疾病，其特征为滑膜增生。许多信号通路与 RA 的发展和诱发症状有关。值得注意的是，RA 患者的蛋白质瓜氨酸化和针对瓜氨酸化蛋白的自身抗体增加。全基因组关联研究表明，肽基精氨酸脱亚氨酶 4（PADI4）是一种在 RA 滑膜中参与瓜氨酸化的酶。针对瓜氨酸化蛋白的自身抗体被用作 RA 患者的诊断标志物。与瓜氨酸化蛋白相关的功能被认为会引发自身免疫，但 PADI4 介导的瓜氨酸化的调节机制尚不清楚。该研究小组之前从 RA 滑膜中克隆了一种 E3 泛素连接酶，即滑膜细胞素（SYVN1），表明 SYVN1 在滑膜细胞增生中起关键作用。数据表明，涉及 SYVN1 的内质网（ER）相关降解系统可能在滑膜细胞增殖中具有重要作用。此外，通过调节 ER 应激信号和蛋白质质量控制，SYVN1 介导的泛素化与纤维化、炎症和细胞因子产生有关。本研究探讨了代表性的翻译后信号过程、瓜氨酸化和泛素化之间的串扰。结果显示，PADI4 与 SYVN1 直接相互作用，而过表达 PADI4 抑制了蛋白质的泛素化。因此，PADI4 诱导的 ER 应激减少可能通过抑制 RA 滑膜细胞的增殖信号来阻断慢性 RA 的发生。
