Department of Biological Sciences, The University of Toledo, Toledo, OH, USA.
Department of Biological Sciences, The University of Toledo, Toledo, OH, USA.
Cytokine. 2017 Nov;99:186-193. doi: 10.1016/j.cyto.2017.05.002. Epub 2017 Jul 29.
The retinoic acid-inducible gene-I (RIG-I)-like helicases (RLH)s are cytoplasmic pattern recognition receptors expressed in both immune and non-immune cells that are essential for detection of intracellular RNA products, primarily of viral origin. Upon binding to viral RNA, RLHs interact with mitochondrial antiviral signaling protein (MAVS) to activate interferon (IFN)-mediated antiviral responses. The RLH/MAVS signaling pathway is regulated by ubiquitination/deubiquitination, in which several ubiquitin-editing proteins play critical roles. The really interesting new gene (RING) finger protein 114 (RNF114) was originally identified as a psoriasis susceptibility gene broadly expressed in human tissues. Earlier studies implicated RNF114 in regulating cellular dsRNA responses, cell cycle progression, NF-κB activity and T-cell activation. We found that RNF114 inhibited cellular dsRNA responses and RLH-mediated IFN production. RNF114 functioned as an E3 ubiquitin ligase, and MAVS was identified as a potential target for RNF114-mediated polyubiquitination and degradation. Splenocytes and blood harvested from RNF114 KO showed increased basal IFN level and sensitized responses to dsRNA. However, RNF114 knockout mice failed to exhibit enhance resistance to infection by two acute RNA viruses. These data suggested the potential physiological function of RNF114 in inflammation and host antiviral responses, but demonstrate complexity in the regulation of innate immunity by ubiquitin ligases.
维甲酸诱导基因-I（RIG-I）样解旋酶（RLH）是表达于免疫和非免疫细胞中的细胞质模式识别受体，对于检测细胞内 RNA 产物（主要来源于病毒）至关重要。RLH 与线粒体抗病毒信号蛋白（MAVS）结合后，可激活干扰素（IFN）介导的抗病毒反应。RLH/MAVS 信号通路受到泛素化/去泛素化的调控，其中几种泛素修饰蛋白发挥着关键作用。RING 指蛋白 114（RNF114）最初被鉴定为一种银屑病易感基因，广泛表达于人体组织中。早期研究表明 RNF114 参与调节细胞内双链 RNA 反应、细胞周期进程、NF-κB 活性和 T 细胞激活。我们发现 RNF114 抑制细胞内双链 RNA 反应和 RLH 介导的 IFN 产生。RNF114 作为一种 E3 泛素连接酶发挥作用，MAVS 被鉴定为 RNF114 介导的多泛素化和降解的潜在靶标。RNF114 敲除的脾细胞和血液中 IFN 水平升高，对双链 RNA 的反应更为敏感。然而，RNF114 敲除小鼠并未表现出对两种急性 RNA 病毒感染的增强抵抗力。这些数据表明 RNF114 在炎症和宿主抗病毒反应中具有潜在的生理功能，但也表明泛素连接酶在固有免疫调节中的复杂性。
