Inhibitory effects of ubiquitination of synoviolin by PADI4
Inhibitory effects of ubiquitination of synoviolin by PADI4
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DOI：
10.3892/mmr.2017.7764
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发表时间：
2017-12-01
影响因子：
3.4
通讯作者：
Nakajima, Toshihiro
中科院分区：
文献类型：
--
作者：
Aratani, Satoko;Fujita, Hidetoshi;Nakajima, Toshihiro
类风湿性关节炎（RA）是一种以滑膜增生为特征的慢性炎症性关节疾病。许多信号通路与 RA 的发展和诱发症状相关。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质的自身抗体的产生增加。全基因组关联研究表明，肽基精氨酸脱亚胺酶 4 (PADI4) 是一种参与 RA 滑膜中瓜氨酸化的酶。针对瓜氨酸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可诱导自身免疫，然而，瓜氨酸化通过 PADI4 的调节机制尚不清楚。该小组此前已从 RA 滑膜中克隆了一种 E3 泛素连接酶滑膜蛋白 (SYVN1)，证明 SYVN1 在滑膜增生中发挥着关键作用。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的增殖中发挥重要作用。此外，SYVN1 的泛素化通过调节 ER 应激信号和蛋白质质量控制与纤维化、炎症和细胞因子产生相关。本研究调查了代表性的翻译后信号传导过程、瓜氨酸化和泛素化之间的串扰。结果表明，PADI4 直接与 SYVN1 相互作用，并且 PADI4 的过表达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消除慢性 RA 的发生。
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.